Association of Retinal Age Gap with Arterial Stiffness and Incident Cardiovascular Disease

Background: Retinal parameters could reflect systemic vascular changes. With the advances of deep learning technology, we have recently developed an algorithm to predict retinal age based on fundus images, which could be a novel biomarker for ageing and mortality. Objective: To investigate associations of retinal age gap with arterial stiffness index (ASI) and incident cardiovascular disease (CVD). Methods: A deep learning (DL) model was trained based on 19,200 fundus images of 11,052 participants without any past medical history at baseline to predict the retinal age. Retinal age gap (retinal age predicted minus chronological age) was generated for the remaining 35,917 participants. Regression models were used to assess the association between retinal age gap and ASI. Cox proportional hazards regression models and restricted cubic splines were used to explore the association between retinal age gap and incident CVD. Results: We found each one-year increase in retinal age gap was associated with increased ASI (β=0.002, 95% confidence interval [CI]: 0.001-0.003, P<0.001). After a median follow-up of 5.83 years (interquartile range [IQR]: 5.73-5.97), 675 (2.00%) developed CVD. In the fully adjusted model, each one-year increase in retinal age gap was associated with a 3% increase in the risk of incident CVD (hazard ratio [HR]=1.03, 95% CI: 1.01-1.06, P=0.012). In the restricted cubic splines analysis, the risk of incident CVD increased significantly when retinal age gap reached 1.21 (HR=1.05; 95% CI, 1.00-1.10; P-overall <0.0001; P-nonlinear=0.0681). Conclusion: We found that retinal age gap was significantly associated with ASI and incident CVD events, supporting the potential of this novel biomarker in identifying individuals at high risk of future CVD events.

Urine β2-Microglobulin and Retinol-Binding Protein and Renal Disease Progression in IgA Nephropathy

Background: Tubulointerstitial involvement has been reported to have a decisive influence on the progression of IgA nephropathy (IgAN). High levels of urine β2-microglobulin (β2-MG) and retinol-binding protein (RBP) were observed in patients with IgAN with tubulointerstitial lesions. However, their roles in disease progression remain unclear. This study aimed to evaluate the associations of urine β2-MG and RBP with the progression of IgAN.Methods: We retrospectively investigated a cohort of 2,153 patients with IgAN. Clinical and pathological features, outcomes, and urine β2-MG, and RBP at the time of biopsy were collected. The associations, of urine β2-MG and RBP with the composite renal outcome, defined as a decline in estimated glomerular filtration rate (eGFR) of ≥50% from baseline or end-stage renal disease (ESRD), were examined using restricted cubic splines and the Cox proportional hazards models.Results: During a median follow-up of 20.40 months, 140 (6.50%) patients reached the composite renal outcomes. Restricted cubic splines showed that patients with higher urinary β2-MG and RBP levels had worse renal outcomes. The Cox regression analysis revealed that urine β2-MG and RBP were associated with a risk of the composite renal outcome in the multivariate adjusted model [+1 SD for log β2-MG, hazard ratio (HR) = 1.462, 95% CI: 1.136–1.882, p = 0.003; +1 SD for log RBP, HR = 1.972, 95% CI: 1.486–2.617, p = 0.001]. The associations were detectable within patients with baseline eGFR &lt;90 ml/min/1.73 m2 (+1 SD for log β2-MG, HR = 1.657, 95% CI: 1.260–2.180, p &lt; 0.001; +1 SD for log RBP, HR = 1.618, 95% CI: 1.199–2.183, p = 0.002), but not among patients with eGFR ≥90 ml/min/1.73 m2.Conclusion: Higher levels of urine β2-MG and RBP were independent risk factors for renal disease progression in IgAN.

Serum Free Fatty Acids Independently Predict Adverse Outcomes in Acute Heart Failure Patients

Background: Perturbation of energy metabolism exacerbates cardiac dysfunction, serving as a potential therapeutic target in congestive heart failure. Although circulating free fatty acids (FFAs) are linked to insulin resistance and risk of coronary heart disease, it still remains unclear whether circulating FFAs are associated with the prognosis of patients with acute heart failure (AHF).Methods: This single-center, observational cohort study enrolled 183 AHF patients (de novo heart failure or decompensated chronic heart failure) in the Second Affiliated Hospital, Zhejiang University School of Medicine. All-cause mortality and heart failure (HF) rehospitalization within 1 year after discharge were investigated. Serum FFAs were modeled as quartiles as well as a continuous variable (per SD of FFAs). The restricted cubic splines and cox proportional hazards models were applied to evaluate the association between the serum FFAs level and all-cause mortality or HF rehospitalization.Results: During a 1-year follow-up, a total of 71 (38.8%) patients had all-cause mortality or HF rehospitalization. The levels of serum FFAs positively contributed to the risk of death or HF rehospitalization, which was not associated with the status of insulin resistance. When modeled with restricted cubic splines, the serum FFAs increased linearly for the incidence of death or HF rehospitalization. In a multivariable analysis adjusting for sex, age, body-mass index, coronary artery disease, diabetes mellitus, hypertension, left ventricular ejection fraction and N-terminal pro-brain natriuretic peptid, each SD (303.07 μmol/L) higher FFAs were associated with 26% higher risk of death or HF rehospitalization (95% confidence interval, 2–55%). Each increasing quartile of FFAs was associated with differentially elevated hazard ratios for death or HF rehospitalization of 1 (reference), 1.71 (95% confidence interval, [0.81, 3.62]), 1.41 (95% confidence interval, [0.64, 3.09]), and 3.18 (95% confidence interval, [1.53, 6.63]), respectively.Conclusion: Serum FFA levels at admission among patients with AHF were associated with an increased risk of adverse outcomes. Additional studies are needed to determine the causal-effect relationship between FFAs and acute cardiac dysfunction and whether FFAs could be a potential target for AHF management.

Association between interpregnancy interval and pregnancy complications by history of complications: a population-based cohort study

ObjectiveTo examine if the association between interpregnancy interval (IPI) and pregnancy complications varies by the presence or absence of previous complications.Design and settingPopulation-based longitudinally linked cohort study in Western Australia (WA).ParticipantsMothers who had their first two (n=252 368) and three (n=96 315) consecutive singleton births in WA between 1980 and 2015.Outcome measuresWe estimated absolute risks (AR) of preeclampsia (PE) and gestational diabetes (GDM) for 3–60 months of IPI according to history of each outcome. We modelled IPI using restricted cubic splines and reported adjusted relative risk (RRs) with 95% CI at 3, 6, 12, 24, 36, 48 and 60 months, with 18 months as reference.ResultsRisks of PE and GDM were 9.5%, 2.6% in first pregnancies, with recurrence rates of 19.3% and 41.5% in second pregnancy for PE and GDM, respectively. The AR of GDM ranged from 30% to 43% across the IPI range for mothers with previous GDM compared with 2%–8% for mothers without previous GDM. For mothers with no previous PE, greater risks were observed for IPIs at 3 months (RR 1.24, 95% CI 1.07 to 1.43) and 60 months (RR 1.40, 95% CI 1.29 to 1.53) compared with 18 months. There was insufficient evidence for increased risk of PE at shorter IPIs of <18 months for mothers with previous PE. Shorter IPIs of <18 months were associated with lower risk than at IPIs of 18 months for mothers with no previous GDM.ConclusionsThe associations between IPIs and risk of PE or GDM on subsequent pregnancies are modified by previous experience with these conditions. Mothers with previous complications had higher absolute, but lower RRs than mothers with no previous complications. However, IPI remains a potentially modifiable risk factor for mothers with previous complicated pregnancies.

Dose-Response Association Between Dietary Folate and Niacin Intakes With Diabetes Among Chinese Adults: A Cross-Sectional Study

Background This study aimed to examine the relationships between dietary vitamin intakes and the risk of diabetes among Chinese adults. Methods This is a cross-sectional observational study. Demographic and anthropometric data along with information on dietary vitamin intakes were collected and eligible participants were recruited to complete a questionnaire. Binary logistic regression analysis was conducted to examine the associations between dietary vitamin intakes and the risk of diabetes, with adjustment for potential confounders. We also evaluated non-linear dose-response relationships between dietary vitamin intakes and diabetes using adjusted restricted cubic splines. Results Of the 3106 eligible participants, 15.9% had prevalent diabetes, 19.0% in male and 13.7% in female, respectively. The median folate was significantly higher in diabetic patients than in controls (32.030 vs 27.600 µg), while median niacin was significantly lower (7.000 vs 7.900 mg). The binary logistic regression analysis also showed a significant association between dietary folate (Odds ratio (OR)=1.002; 95% confidence interval (CI): 1.000-1.004; P=0.022) and niacin intakes (OR=0.965; 95% CI: 0.944-0.986; P=0.001) with the risk of diabetes after controlling for potential confounders. The plots of restricted cubic splines presented an atypical inverted U-shaped association between dietary folate intake and diabetes. Conclusions The data presented here showed that diabetics had a low intake of vitamins, especially B group vitamins. Dietary folate and niacin intakes tended to be independently related to the risk of diabetes. Nevertheless, this study is observational, and there yet to be large-scale randomized controlled trials which would increase the evidence of the findings.

Albumin-corrected fructosamine predicts all-cause and non-CVD mortality among the very elderly aged ≥ 80 years without diabetes

Background Several guidelines have suggested alternative glycemic markers for hemoglobin A1c among older adults with limited life expectancy or multiple coexisting chronic illnesses. We evaluated associations between fructosamine, albumin-corrected fructosamine (AlbF) and fasting plasma glucose (FPG) and mortality in the diabetic and non-diabetic subpopulations, compared which marker better predicts mortality among participants aged 80 and above. Methods Included were 2,238 subjects from the Healthy Ageing and Biomarkers Cohort Study (2012-2018) and 207 participants had diabetes at baseline. Multivariable Cox proportional hazards regression models investigated the associations of fructosamine, AlbF, FPG and all-cause, cardiovascular disease (CVD), and non-CVD mortality in the diabetic and non-diabetic subpopulations. Restricted cubic splines (RCS) explored potential non-linear relations. C-statistic, integrated discrimination improvement (IDI) and net reclassification improvement (NRI) evaluated the additive value of different glycemic markers to predict mortality. Results Overall, 1,191 deaths were documented during 6,793 person-years of follow-up. In the linear model, per unit increases of fructosamine, AlbF and FPG were associated with higher risk of mortality in non-diabetic participants, with hazard ratios of 1.02 (1.00, 1.05), 1.27 (1.14, 1.42) and 1.04 (0.98, 1.11) for all-cause mortality, and 1.04 (1.00, 1.07), 1.38 (1.19, 1.59) and 1.10 (1.01, 1.19) for non-CVD mortality, respectively. Comparisons indicated AlbF better predicts all-cause and non-CVD mortality in non-diabetic participants with significant improvement in IDI and NRI. Conclusions Higher concentrations of fructosamine, AlbF, and FPG were associated with higher risk of all-cause or non-CVD mortality among very elderly where AlbF may constitute an alternative prospective glycemic predictor of mortality.

Altered serum calcium homeostasis independently predicts mortality in patients with acute coronary syndrome: a retrospective observational cohort study

ObjectivesSerum calcium levels (sCa) were reported to be associated with risk of cardiovascular diseases. The aim of this study was to analyse the association between sCa and long-term mortality in patients with acute coronary syndrome (ACS).DesignA retrospective observational cohort study.SettingSingle-centre study with participants recruited from the local area.ParticipantsA total of consecutive 13 772 patients with ACS were included in this analysis. Patients were divided based on their sCa profile (≤2.1 mmol/L, 2.1–2.2 mmol/L, 2.2–2.3 mmol/L, 2.3–2.4 mmol/L, 2.4–2.5 mmol/L,>2.5 mmol/L) and followed up for a median of 2.96 years (IQR 1.01–4.07).Primary outcomeLong-term all-cause mortality.ResultsDuring a median follow-up period of 2.96 years, patients with sCa ≤2.1 mmol/L had the highest cumulative incidences of all-cause mortality (16.7%), whereas those with sCa 2.4–2.5 mmol/L had the lowest cumulative incidences of all-cause mortality (3.5%). After adjusting for potentially confounding variables, the Cox analysis revealed that compared with the reference group (sCa 2.4–2.5 mmol/L), all the other groups had higher mortality except for the sCa 2.3–2.4 mmol/L group (HR, 1.32, 95% CI 0.93 to 1.87). Restricted cubic splines showed that the relationship between sCa and all-cause mortality seemed to be U shaped. The optimal sCa cut-off point, 2.35 mmol/L, was determined based on the shape of restricted cubic splines.ConclusionsAltered serum calcium homeostasis at admission independently predicts all-cause mortality in patients with ACS. In addition, a U-shaped relationship between sCa and all-cause mortality exists, and maintaining sCa at approximately 2.35 mmol/L may minimise the risk of mortality.

Computational correction of cell-specific gene-independent effects in CRISPR-Cas9 essentiality screens: REStricted CUbic SplinEs with Mixed Models (RESCUE-MM)

Increased gene copy number has been associated with a greater antiproliferative response upon genome editing, regardless of the true essentiality profile of the targeted gene. Many methods have been developed to adjust for genomic copy number technical artifacts. Existing methods use a two-step correction by pre-processing the data prior to the final analysis. It has been shown that two-step corrections can produce unreliable results, due to the creation of a correlation structure in the corrected data. If this structure is unaccounted for, gene-essentiality levels can be inflated or underestimated, affecting the False Discovery Rate (FDR). We propose a one-step correction using restricted cubic splines (RCS) to be a simpler alternative which reduces the bias in downstream analyses. Moreover, most existing methods combine guide-level results to yield gene-level estimates which can misrepresent the true gene essentiality profile depending on the guide-averaging method. Our model-based approach (RESCUE-MM) for copy number correction provides a more flexible framework that allows for guide-level essentiality estimation while accommodating more complex designs with grouped data. We provide comparisons to existing copy number correction methods and suggest how to include copy number adjustment in a one-step correction fashion in multiple experimental designs.

Abdominal adipose tissue radiodensity is associated with survival after colorectal cancer

ABSTRACT Background Adipose tissue radiodensity may have prognostic importance for colorectal cancer (CRC) survival. Lower radiodensity is indicative of larger adipocytes, while higher radiodensity may represent adipocyte atrophy, inflammation, or edema. Objectives We investigated associations of adipose tissue radiodensity and longitudinal changes in adipose tissue radiodensity with mortality among patients with nonmetastatic CRC. Methods In 3023 patients with stage I–III CRC, radiodensities of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were quantified from diagnostic computed tomography (CT) images. There were 1775 patients with follow-up images available. Cox proportional hazards models and restricted cubic splines were used to examine associations of at-diagnosis values and of longitudinal changes in VAT and SAT radiodensities with risks of death after adjusting for potential confounders, including body size and comorbidities. Results VAT and SAT radiodensities were linearly associated with all-cause mortality: the HRs for death per SD increase were 1.21 (95% CI, 1.11–1.32) for VAT radiodensity and 1.18 (95% CI, 1.11–1.26) for SAT radiodensity. Changes in adipose tissue radiodensity had curvilinear associations with risks of death. The HR for an increase in VAT radiodensity of at least 1 SD was 1.53 (95% CI, 1.23–1.90), while the HR for a decrease of at least 1 SD was nonsignificant at 1.11 (95% CI, 0.84–1.47) compared with maintaining radiodensity within 1 SD of baseline. Similarly, increases (HR, 1.88; 95% CI, 1.48–2.40) but not decreases (HR, 1.20; 95% CI, 0.94–1.54) in SAT radiodensity significantly increased the risk of death compared with no change in radiodensity. Conclusions In patients with nonmetastatic CRC, adipose tissue radiodensity is a novel risk factor for total mortality that is independent of BMI and changes in body weight.