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.

Associations between Socio-Economic Status and Unfavorable Social Indicators of Child Wellbeing; a Neighbourhood Level Data Design

Background: Living in deprivation is related to ill health. Differences in health outcomes between neighbourhoods may be attributed to neighbourhood socio-economic status (SES). Additional to differences in health, neighbourhood differences in child wellbeing could also be attributed to neighbourhood SES. Therefore, we aimed to investigate the association between neighbourhood deprivation, and social indicators of child wellbeing. Methods: Aggregated data from 3565 neighbourhoods in 390 municipalities in the Netherlands were eligible for analysis. Neighbourhood SES scores and neighbourhood data on social indicators of child wellbeing were used to perform repeated measurements, with one year measurement intervals, over a period of 11 years. Linear mixed models were used to estimate the associations between SES score and the proportion of unfavorable social indicators of child wellbeing. Results: After adjustment for year, population size, and clustering within neighbourhoods and within a municipality, neighbourhood SES was inversely associated with the proportion of ‘children living in families on welfare’ (estimates with two cubic splines: −3.59 [CI: −3.99; −3.19], and −3.00 [CI: −3.33; −2.67]), ‘delinquent youth’ (estimate −0.26 [CI: −0.30; −0.23]) and ‘unemployed youth’ (estimates with four cubic splines: −0.41 [CI: −0.57; −0.25], −0.58 [CI: −0.73; −0.43], −1.35 [−1.70; −1.01], and −0.96 [1.24; −0.70]). Conclusions: In this study using repeated measurements, a lower neighbourhood SES was significantly associated with a higher prevalence of unfavorable social indicators of child wellbeing. This contributes to the body of evidence that neighbourhood SES is strongly related to child health and a child’s ability to reach its full potential in later life. Future studies should consist of larger longitudinal datasets, potentially across countries, and should attempt to take the interpersonal variation into account with more individual-level data on SES and outcomes.

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.

Curved layer path planning on a 5-axis 3D printer

Purpose This paper aims to provide an approach to print shell-type objects using a 5-axis printer. The proposed approach takes advantage of the two additional printer degrees of freedom to provide a curved layer path planning strategy. Design/methodology/approach This paper addresses curved layer path planning on a 5-axis printer. This printer considers movements along the three usual axes together with two additional axes at the printing table (rotation and tilt), allowing to build more complex and reliable objects. Curved layer path planning is considered where polygons obtained from the slicing stage are approximated by linear and cubic splines. The proposed printing strategy consists in building an inner core supporting structure followed by outer curved layers. Findings The curved layer path planning strategy is validated for shell-type objects by considering a 5-axis printer simulator. An example with an aeronautic object is presented to illustrate the proposed approach. Originality/value The paper presents an approach to curved layer path planning on a 5-axis printer, for shell-type objects.

Baseline Neutrophil-to-Lymphocyte Ratio Is Independently Associated With 90-Day Transplant-Free Mortality in Patients With Cirrhosis

Background: Patients with cirrhosis have an increased risk of short-term mortality, however, few studies quantify the association between neutrophil-to-lymphocyte ratio (NLR) and 90-day transplant-free mortality in cirrhotic patients.Methods: We prospectively analyzed 3,970 patients with chronic liver diseases from two multicenter cohorts in China (January 2015 to December 2016 and July 2018 to January 2019). Restricted cubic splines (RCS) were used to analyze the relation of NLR and all-causes 90-day transplant-free mortality in cirrhosis.Results: A total of 2,583 cirrhotic patients were enrolled in our study. Restricted cubic splines showed that the odds ratio (OR) of all causes 90-day transplant-free mortality started to increase rapidly until around NLR 6.5, and then was relatively flat (p for non-linearity &lt;0.001). The risk of 90-day transplant-free mortality in cirrhotic patients with NLR &lt; 6.5 increased with an increment of 23% for every unit increase in NLR (p &lt; 0.001). The patients with NLR &lt; 4.5 had the highest risk (OR: 2.34, 95% CI 1.66–3.28). In multivariable-adjusted stratified analyses, the increase in the incidence of 90-day transplant-free mortality with NLR increasing was consistent (OR &gt;1.0) across all major prespecified subgroups, including infection group (OR: 1.04, 95% CI 1.00–1.09) and non-infection (OR: 1.06, 95% CI 1.02–1.11) group. The trends for NLR and numbers of patients with organ failure varied synchronously and were significantly increased with time from day 7 to day 28.Conclusions: We found a non-linear association between baseline NLR and the adjusted probability of 90-day transplant-free mortality. A certain range of NLR is closely associated with poor short-term prognosis in patients with cirrhosis.