Dietary inflammatory potential and arterial stiffness in a French cohort: Insights from the STANISLAS study.

BACKGROUND AND AIMS: Chronic inflammation plays a key role in arterial stiffness pathogenesis. Dietary components can display anti- or pro-inflammatory properties. Nonetheless, the association between the diet's overall inflammatory potential and arterial stiffness is unclear. This study aimed to assess the association between the diet's overall inflammatory potential and arterial stiffness assessed by carotid-femoral pulse wave velocity (cfPWV). METHODS AND RESULTS: This cross-sectional study included 1307 participants from the STANISLAS family cohort study. Dietary data were collected using a validated food frequency questionnaire. The adapted dietary inflammatory index (ADII) score was calculated to assess the inflammatory potential of the participants' diet. The association of ADII score quartile with cfPWV was assessed using IPW-weighted linear mixed models with random family effect. The median (Q1-Q3) ADII score was 0.45 (-1.57, 2.04). Participants exhibiting higher ADII scores demonstrated elevated energy intake, dietary saturated fat, and ultra-processed foods. Conversely, individuals with lower ADII scores exhibited higher vitamins and omega intakes, and a higher diet quality, as assessed by the DASH score. Despite these observations from the descriptive analyses, ADII score quartiles were not significantly associated with cfPWV (ß(95% CI) were 0.01 (-0.02,0.04) for Q2, 0.02 (-0.01,0.05) for Q3, and 0.02 (-0.01,0.05) for Q4 compared to Q1). CONCLUSION: In this cross-sectional study, participants had a relatively modest consumption of pro-inflammatory foods, no substantial associations were observed between the diet inflammatory potential and arterial stiffness. Further longitudinal studies in larger cohorts are needed to better understand the link between inflammatory diet and arterial stiffness.

Impact of text contrast polarity on the retinal activity in myopes and emmetropes using modified pattern ERG.

Environmental factors favoring myopia development are still being studied and there is accumulating evidence for a significant role of nearwork. Recently, reading standard black-on-white text was found to activate the retinal OFF pathway and induce choroidal thinning, which is associated with myopia onset. Contrarily, reading white-on-black text led to thicker choroids, being protective against myopia. Respective effects on retinal processing are yet unknown. Here, we exploratively assessed the impact of contrast polarity on the retinal activity and possible interactions with eccentricity and refractive error. We recorded pattern electroretinograms in myopic and emmetropic adults while presenting a dead leaves stimulus (DLS), overlaid by masks of different size in ring or circle shape, either filled with uniform gray or text of inverted or standard contrast. In myopes, retinal responses for DLS with standard and inverted contrast were larger when the perifovea was stimulated (6-12 deg), however, including the fovea resulted in smaller amplitudes for inverted contrast than in emmetropes. The retina of emmetropes was more sensitive to inverted contrast than to standard and gray within 12 deg, but most sensitive for gray in the perifovea. This demonstrates that the refractive error influences the sensitivity to text contrast polarity, with a special role of the peripheral retina, which is in line with previous studies about blur sensitivity. Defining whether the differences derive from retinal processing or anatomical features of a myopic eye requires further investigation. Our approach might be a first step to explain how nearwork promotes the eye's elongation.

Birth weight and subclinical cardiovascular and renal damage in a population-based study (the STANISLAS cohort study).

OBJECTIVE: Although preterm-born and low-birth-weight individuals have an increased risk of cardiovascular diseases in adulthood, little is known regarding early cardiovascular and renal damage (CVRD) or hypertension in adulthood. Our study investigated the association of birth weight with early CVRD markers as well as the heritability of birth weight in an initially healthy family-based cohort. METHODS: This study was based on 1028 individuals from the familial longitudinal STANISLAS cohort (399 parents/629 children) initiated in 1993-1995, with a fourth examination conducted in 2011-2016. Analyses performed at the fourth visit included pulse-wave velocity, central pressure, ambulatory blood pressure, hypertension status, diastolic dysfunction/distensibility, left ventricular mass indexed (LVMI), carotid intima-media thickness and kidney damage. The family structure of the cohort allowed birth weight heritability estimation. RESULTS: Mean (±SD) birth weight was 3.3 ±â€Š0.6 kg. Heritability was moderate (42-44%). At the fourth visit, individuals were 37 years old (32.0-57.0), 56% were women and 13% had antihypertensive treatment. Birth weight was strongly and negatively associated with hypertension [odds ratio (OR) 95% confidence interval (CI) 0.61 (0.45-0.84)]. A nonlinear association was found with LVMI, participants with a birth weight greater than 3 kg having a higher LVMI. A positive association ( ß 95% CI 5.09 (1.8-8.38)] was also observed between birth weight and distensibility for adults with normal BMI. No associations were found with other CVRD. CONCLUSION: In this middle-aged population, birth weight was strongly and negatively associated with hypertension, and positively associated with distensibility in adults with normal BMI and with LVMI for higher birth weights. No associations were found with other CVRD markers.

Monocular transcorneal electrical stimulation induces ciliary muscle thickening in contralateral eye.

Transcorneal electrical stimulation (TES) is used as therapy for retinal diseases such as retinitis pigmentosa (RP) and was suggested for assessing retinal sensitivity by determining phosphene thresholds, subjective luminance impressions caused by retinal stimulation. Further applications concerned the accommodation process, revealing an improved accommodative amplitude in presbyopic eyes after TES treatment. The respective changes of the ciliary muscle (CM), the structure most important for near vision, during TES are yet unknown. In a pilot study, we aimed to assess whether monocular TES leads to morphological and functional CM changes and whether central accommodation control is affected. Ten healthy, near-emmetropic adults participated in the trial (4 females, age 26.3 ± 3.6 years). Using a wavefront and a stimulus generator, a biphasic square-wave stimulus (2 s positive and 6 s negative amplitude) of 0 µA average current was produced and transferred to the eye by means of a Dawson-Trick & Litzkow electrode. Prior to the stimulation, an individual determination of phosphene thresholds served to define individual TES current amplitudes, which ranged between 60 and 100 µA. Optical coherence tomography (OCT) imaging of the right eye's temporal ciliary muscle was performed before and during ipsi- as well as contralateral monocular TES in randomized order in the morning and afternoon of the same day. During imaging, subjects fixated a target at 4 m distance and refraction was simultaneously recorded via eccentric infrared photorefraction. OCT images were assessed using previously published custom-developed software, allowing the definition of selective CM thickness (CMT) readings, and plotting of continuous CMT profiles along the muscle border. CMT profiles revealed that both stimulations, on the ipsi- and contralateral eye, induced a thickening of the CM compared to the non-stimulated state. The selective CMT readings confirmed a significant increase with ipsi- (31 ± 30 µm; p = 0.010) and contralateral (25 ± 16 µm; p = 0.001) TES. However, refraction during far vision was not significantly affected by either stimulation (ipsilateral [n = 5]: median Δw/-w/o = 0 D; contralateral [n = 7]: Δw/-w/o = 0.13 D). Pupil size on average increased during TES, but without reaching significance (ipsilateral [n = 5] median Δw/-w/o = 0.23 mm, contralateral [n = 7] Δw/-w/o = 0.39 mm). Ipsilateral CM thickening could be explained by local changes within the stimulated ciliary muscle, such as increased blood flow or interstitial fluid rise induced by TES. However, the CMT increase in the right eye when TES was performed contralaterally, on the left eye, indicates an involvement of the central control circuit of accommodation. Further possible explanations for this finding are a synchronization of neuronal activities in the visual pathway, the release of vasoactive neuropeptides, or effects on the central blood pressure regulation. Given a neuromodulation effect on the CM function, TES might have implications for children with accommodation insufficiencies and as additional therapy in myopia control management, e.g. in combination with multifocal contact lens treatment. Our study is important for the clinical application of TES, and the outcome might add crucial knowledge to the current understanding of the accommodation process and inform research and treatment of both myopia and presbyopia.

Associations of childhood adiposity with adult intima-media thickness and inflammation: a 20-year longitudinal population-based cohort.

BACKGROUND: The associations between childhood adiposity and adult increased carotid intima-media thickness (cIMT) have been well established, which might be corroborated by the association between adiposity in children and inflammation in adults. However, longitudinal data regarding biological pathways associated with childhood adiposity are lacking. METHODS: The current study included participants from the STANISLAS cohort who had adiposity measurements at age 5-18 years [ N  = 519, mean (SD) age, 13.0 (2.9) years; 46.4% male], and who were measured with cIMT, vascular-related and metabolic-related proteins at a median follow-up of 19 ±â€Š2 years. BMI, waist-to-height ratio and waist circumference were converted to age-specific and sex-specific z -scores. RESULTS: A minority of children were overweight/obese (16.2% overweight-BMI z -score >1; 1.3% obesity- z -score >2). Higher BMI, waist-height ratio and waist circumference in children were significantly associated with greater adult cIMT in univariable analysis, although not after adjusting for C-reactive protein. These associations were more pronounced in those with consistently high adiposity status from childhood to middle adulthood. Participants with higher adiposity during childhood (BMI or waist-height ratio) had higher levels of insulin-like growth factor-binding protein-1, protein-2, matrix metalloproteinase-3, osteopontin, hemoglobin and C-reactive protein in adulthood. Network analysis showed that IL-6, insulin-like growth factor-1 and fibronectin were the key proteins associated with childhood adiposity. CONCLUSION: In a population-based cohort followed for 20 years, higher BMI or waist-to-height ratio in childhood was significantly associated with greater cIMT and enhanced levels of proteins reflective of inflammation, supporting the importance of inflammation as progressive atherosclerosis in childhood adiposity.

Association between eating behaviour and 13-year cardiovascular damages in the initially healthy STANISLAS cohort.

AIMS: Several dimensions of eating behaviour (EB), such as restrained eating (RE), appear to be cross-sectionally associated with certain cardiovascular (CV) diseases and metabolic risk factors although little is known regarding longitudinal associations. This study aimed to assess the associations between EB and CV damage or metabolic syndrome after 13 years, in initially healthy individuals. METHODS AND RESULTS: This study included 1109 participants from the familial STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort study. Emotional eating (EmE), RE, and external eating were assessed using the Dutch Eating Behaviour Questionnaire. Metabolic syndrome and CV damages such as carotid-femoral pulse-wave velocity (cfPWV), left ventricular mass, carotid intima-media thickness, and diastolic dysfunction (DD) were measured after a period of 13 years. Mixed model analysis with a family random effect and adjustment for age, sex, education, temporal gap, physical activity, metabolic factors at baseline, and the onset of CV disease during follow-up, and mediation analysis were performed in adults and adolescents separately. Among adults, EmE was associated with a 38% increased risk of DD 13 years later [odds ratio = 1.38 (1.05; 1.83)]. Stress level mediated 31.9% of this association (P = 0.01). Emotional eating was positively associated with cfPWV (ß=0.02 [0.01; 0.04]). External eating was slightly associated with lower cfPWV (ß=-0.03 [-0.05; -0.01]). No associations were observed between EB dimensions and metabolic syndrome. Energy intake was not found to be a mediator of any associations. CONCLUSION: Our results suggest that CV prevention should also take into account EB and include emotion regulation skills teaching.

The association of three dimensions of eating behaviour [emotional eating, restrained eating, and external eating] with 13 years later cardiovascular damages have been investigated in the initially healthy STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) cohort. Emotional eating was associated with higher pulse-wave velocity and an increased risk of diastolic dysfunction. External eating was associated with lower pulse-wave velocity. Stress level was found to be a mediator of the association found between emotional eating and diastolic dysfunction.

Performance of the Deep Neural Network Ciloctunet, Integrated with Open-Source Software for Ciliary Muscle Segmentation in Anterior Segment OCT Images, Is on Par with Experienced Examiners.

Anterior segment optical coherence tomography (AS-OCT), being non-invasive and well-tolerated, is the method of choice for an in vivo investigation of ciliary muscle morphology and function. The analysis requires the segmentation of the ciliary muscle, which is, when performed manually, both time-consuming and prone to examiner bias. Here, we present a convolutional neural network trained for the automatic segmentation of the ciliary muscle in AS-OCT images. Ciloctunet is based on the Freiburg U-net and was trained and validated using 1244 manually segmented OCT images from two previous studies. An accuracy of 97.5% for the validation dataset was achieved. Ciloctunet's performance was evaluated by replicating the findings of a third study with 180 images as the test data. The replication demonstrated that Ciloctunet performed on par with two experienced examiners. The intersection-over-union index (0.84) of the ciliary muscle thickness profiles between Ciloctunet and an experienced examiner was the same as between the two examiners. The mean absolute error between the ciliary muscle thickness profiles of Ciloctunet and the two examiners (35.16 µm and 45.86 µm) was comparable to the one between the examiners (34.99 µm). A statistically significant effect of the segmentation type on the derived biometric parameters was found for the ciliary muscle area but not for the selective thickness reading ("perpendicular axis"). Both the inter-rater and the intra-rater reliability of Ciloctunet were good to excellent. Ciloctunet avoids time-consuming manual segmentation, thus enabling the analysis of large numbers of images of ample study cohorts while avoiding possible examiner biases. Ciloctunet is available as open-source.

Determinants of Antiretroviral Treatment Success and Adherence in People With Human Immunodeficiency Virus Treated for Tuberculosis.

Background: In people with human immunodeficiency virus [HIV] presenting with advanced disease, rates of virologic success may be lower than expected. The Reflate TB2 trial did not show non-inferiority of raltegravir versus efavirenz in people with HIV (PWH) treated for tuberculosis. We aimed to identify factors associated with virologic success and higher adherence in the trial. Methods: In this analysis, we included participants enrolled in the Reflate TB2 trial with adherence data available. The primary outcome was virologic success (HIV-1 ribonucleic acid [RNA] <50 copies/mL) at week 48, and the secondary outcome was adherence as assessed by the pill count adherence ratio. We used logistic regression to study determinants of virologic success and optimal adherence in 2 separate analyses. Results: Four hundred forty-four participants were included in the present analysis. Over the 48-week follow-up period, 290 of 444 (65%) participants had a pill count adherence ratio ≥95%. At week 48, 288 of 444 (65%) participants were in virologic success. In the multivariate analysis, female sex (adjusted odds ratio [aOR], 1.77; 95% confidence interval [CI], 1.16-2.72; P = .0084), lower baseline HIV-1 RNA levels (<100 000; aOR, 2.29; 95% CI, 1.33-3.96; P = .0087), and pill count adherence ratio ≥95% (aOR, 2.38; 95% CI, 1.56-3.62; P < .0001) were independently associated with virologic success. Antiretroviral pill burden was the only factor associated with pill count adherence ratio ≥95% (OR, 0.81; 95% CI, .71-.92; P = .0018). Conclusions: In PWH with tuberculosis receiving raltegravir or efavirenz-based regimens, female sex, optimal adherence, and baseline HIV-1 RNA <100 000 copies/mL were associated with virologic success, and the number of antiretroviral tablets taken daily was a strong predictor of adherence.

Fatty acid desaturase genetic variations and dietary omega-3 fatty acid intake associate with arterial stiffness.

Aims: Long-chain polyunsaturated fatty acids (PUFAs) generate diverse bioactive lipid mediators, which tightly regulate vascular inflammation. The effects of omega-3 PUFA supplementation in cardiovascular prevention however remain controversial. In addition to direct dietary intake, fatty acid desaturases (FADS) determine PUFA levels. Increased arterial stiffness represents an independent predictor of mortality and cardiovascular events. The aim of the present study was to determine the association of PUFA intake, FADS1 genotype, and FADS expression with arterial stiffness. Methods and results: A cross-sectional population-based cohort study of 1464 participants without overt cardiovascular disease was conducted. Dietary intake was assessed using a food frequency questionnaire. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), and the FADS1 locus variant was determined. Blood cell transcriptomics was performed in a subset of 410 individuals. Pulse wave velocity was significantly associated with the FADS1 locus variant. Differential associations between PWV and omega-3 PUFA intake were observed depending on the FADS1 genotype. High omega-3 PUFA intake attenuated the FADS1 genotype-dependent associations. Carriers of the minor FADS1 locus variant exhibited increased expression of FADS2, which is associated with PWV. Conclusion: Taken together, these findings point to FADS1 genotype-dependent associations of omega-3 PUFA intake on subclinical cardiovascular disease. These findings may have implications for identifying responders and non-responders to omega-3 PUFA supplementation and open up for personalized dietary counselling in cardiovascular prevention.

Novel Three-Dimensional and Biocompatible Lift-Off Method for Selective Metallization of a Scleral Contact Lens Electrode for Biopotential Detection.

Presbyopia describes the eye's physiological loss of the ability to see close objects clearly. The adaptation to different viewing distances, termed accommodation, is achieved by a change in the curvature of the eye lens induced by the ciliary muscle. A possible approach to correct presbyopia could be to detect the ciliary muscle's neuromuscular signals during accommodation and transfer these signals electronically to a biomimetic, micro-optical system to provide the necessary refractive power. As a preliminary step toward such a described system, a novel three-dimensional and biocompatible lift-off method was developed. In addition, the influence of the distance between the electrically conducting surfaces of the lens on the accommodated signal amplitudes was investigated. Compared to the conventional masking methods, this process has the advantage that three-dimensional surfaces can be masked with biocompatible gelling sugar by utilizing a direct writing process with a dispensing robot. Since gelling sugar can be used at room temperature and is water-soluble, the process presented is suitable for materials that should not be exposed to organic solvents or excessively high temperatures. Apart from investigating the shrinkage behavior of the gelling sugar during the physical vapor deposition (PVD) coating process, this paper also describes the approaches used to partially coat a commercial scleral contact lens with an electrically conductive material. It was shown that gelling sugar withstands the conditions during the PVD processes and a successful lift-off was performed. To investigate the influence of the spacing between the electrically conductive regions of the contact lens on the measured signals, three simplified electrode configurations with different distances were fabricated using a 3D printer. By testing these in an experimental setup, it could be demonstrated that the distance between the conductive surfaces has a significant influence on the amplitude. Regarding the described lift-off process using gelling sugar, it was found that the dispensing flow rate has a direct influence on the line uniformity. Future work should address the influence of the viscosity of the gelling sugar as well as the diameter of the cannula. It is assumed that they are the prevailing limitations for the lateral resolution.

Probiotic Intake and Inflammation in Patients With Chronic Kidney Disease: An Analysis of the CKD-REIN Cohort.

Background and Aims: Little is known about the effects of probiotics on inflammation in the context of chronic kidney disease (CKD). We investigated the association between probiotic intake and inflammation in patients with moderate-to-advanced CKD. Methods: We performed a cross-sectional study of 888 patients with stage 3-5 CKD and data on serum C-reactive protein (CRP) levels and a concomitant food frequency questionnaire. We estimated the odds ratios (ORs) [95% confidence interval (CI)] for various CRP thresholds (>3, >4, >5, >6, and >7 mg/L) associated with three intake categories (no yoghurt, ordinary yoghurt, and probiotics from yoghurts or dietary supplements) and two frequency categories (daily or less than daily). Results: The 888 study participants (median age: 70; men: 65%) had a median estimated glomerular filtration rate of 28.6 mL/min/1.73 m2 and a median [interquartile range] CRP level of 3.0 [1.6, 7.0] mg/L. Fifty-seven percent consumed ordinary yoghurt and 30% consumed probiotic yoghurt. The median intake frequency for yoghurt and probiotics was 7 per week. Relative to participants not consuming yoghurt, the ORs [95% CI] for CRP > 6 or >7 mg/L were significantly lower for participants consuming ordinary yoghurt (0.58 [0.37, 0.93] and 0.57 [0.35, 0.91], respectively) and for participants consuming probiotics (0.54 [0.33, 0.9] and 0.48 [0.28, 0.81], respectively), independently of age, sex, body mass index, CKD stage, cardiovascular disease, and fibre, protein and total energy intakes. The ORs were not significantly lower for CRP thresholds >3, >4, and >5 mg/L and were not significantly greater in daily consumers than in occasional consumers. Conclusion: We observed independent associations between the consumption of yoghurt or probiotics and lower levels of inflammation in patients with CKD. There was no evidence of a dose-effect relationship. Clinical Trial Registration: [https://www.clinicaltrials.gov/ct2/show/NCT03381950], identifier [NCT03381950].

Weak Association Between Genetic Markers of Hyperuricemia and Cardiorenal Outcomes: Insights From the STANISLAS Study Cohort With a 20-Year Follow-Up.

Background Hyperuricemia is associated with poor cardiovascular outcomes, although it is uncertain whether this relationship is causal in nature. This study aimed to: (1) assess the heritability of serum uric acid (SUA) levels, (2) conduct a genome-wide association study on SUA levels, and (3) investigate the association between certain single-nucleotide polymorphisms and target organ damage. Methods and Results The STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) study cohort is a single-center longitudinal cohort recruited between 1993 and 1995 (visit 1), with a last visit (visit 4 [V4]) performed ≈20 years apart. Serum lipid profile, SUA, urinary albumin/creatinine ratio, estimated glomerular filtration rate, 24-hour ambulatory blood pressure monitoring, transthoracic echocardiography, pulse wave velocity, and genotyping for each participant were assessed at V4. A total of 1573 participants were included at V4, among whom 1417 had available SUA data at visit 1. Genome-wide association study results highlighted multiple single-nucleotide polymorphisms on the SLC2A9 gene linked to SUA levels. Carriers of the most associated mutated SLC2A9 allele (rs16890979) had significantly lower SUA levels. Although SUA level at V4 was highly associated with diabetes, prediabetes, higher body mass index, CRP (C-reactive protein) levels, estimated glomerular filtration rate variation (visit 1-V4), carotid intima-media thickness, and pulse wave velocity, rs16890979 was only associated with higher carotid intima-media thickness. Conclusions Our findings demonstrate that rs16890979, a genetic determinant of SUA levels located on the SLC2A9 gene, is associated with carotid intima-media thickness despite significant associations between SUA levels and several clinical outcomes, thereby lending support to the hypothesis of a link between SUA and cardiovascular disease.

Association of Serum Phosphate with Efficacy of Statin Therapy in Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Statins are less efficacious in reducing cardiovascular disease risk in patients on dialysis than in the general population. Recent experimental data showed that phosphate excess promotes cellular de novo cholesterol synthesis through 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activation. Whether this mechanism might account for the resistance of patients on dialysis to statins has not yet been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this post hoc analysis, we examined the efficacy of statin treatment according to serum phosphate levels in the patients on dialysis who were participants of the A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial using serum phosphate levels at baseline and during the trial course. We first classified the patients by groups of similar phosphate trajectories over time and tested whether phosphate as a longitudinal exposure (summarized by the identified trajectory groups) modulated the occurrence of major adverse cardiovascular events and all-cause death. We replicate the analysis in the Deutsche Diabetes Dialyze Studie (4D) trial. RESULTS: In the AURORA trial, using multivariable analysis, we found that the treatment effect of statin on major adverse cardiovascular events and all-cause death was significant and protective effects in patients with low values of serum phosphate gradually faded for higher phosphate levels >5 mg/dl. A similar lack of statin treatment efficacy for both outcomes was observed with high baseline phosphate levels (>5 mg/dl). In the 4D trial, we found a comparable but not significant trend toward losing treatment efficacy in the presence of high serum phosphate levels for both outcomes. CONCLUSIONS: Our results demonstrated the limited treatment efficacy of statins in patients on dialysis in the presence of hyperphosphatemia.

Impact of natriuretic peptide polymorphisms on diastolic and metabolic function in a populational cohort: insights from the STANISLAS cohort.

AIMS: Elevated brain natriuretic peptide (BNP) and the N-terminal fragment of its pro-hormone (NT-proBNP) have become established biomarkers for heart failure and are associated with cardiovascular morbidity and mortality. Investigating sources of inter-individual heterogeneity, particularly genetic factors, could help better identify patients at risk of future cardiovascular disease. The aim of this study was to estimate the heritability of circulating NT-proBNP levels, to perform a genome-wide association study (GWAS) and gene-candidate analysis focused on NPPB-NPPA genes on these levels, and to examine their association with cardiovascular or metabolic outcomes. METHODS AND RESULTS: A total of 1555 individuals from the STANISLAS study were included. The heritability of circulating NT-proBNP levels was estimated at 15%, with seven single nucleotide polymorphisms (SNPs) reaching the significant threshold in the GWAS. All above SNPs were located on the same gene cluster constituted of MTHFR, CLCN6, NPPA, NPPB, and C1orf167. NPPA gene expression was also associated with NT-proBNP levels. Moreover, six other SNPs from NPPA-NPPB genes were associated with diastolic function (lateral e' on echocardiography) and metabolic features (glycated haemoglobin). CONCLUSIONS: The heritability of natriuretic peptides appears relatively low (15%) and mainly based on the same gene cluster constituted of MTHFR, CLCN6, NPPA, NPPB, and C1orf167. Natriuretic peptide polymorphisms are associated with natriuretic peptide levels and diastolic function. These results suggest that natriuretic peptide polymorphisms may have an impact in the early stages of cardiovascular and metabolic disease.

Water intake and progression of chronic kidney disease: the CKD-REIN cohort study.

BACKGROUND: Optimal daily water intake to prevent chronic kidney disease (CKD) progression is unknown. Taking the kidney's urine-concentrating ability into account, we studied the relation of kidney outcomes in patients with CKD to total and plain water intake and urine volume. METHODS: Including 1265 CKD patients [median age 69 years; mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] from the Chronic Kidney Disease-Renal Epidemiology and Information Network cohort (2013-19), we assessed fluid intake at baseline interviews, collected 24-h urine volumes and estimated urine osmolarity (eUosm). Using Cox and then linear mixed models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for kidney failure and eGFR decline associated with hydration markers, adjusting for CKD progression risk factors and eUosm. RESULTS: Patients' median daily intake was 2.0 L [interquartile range (IQR) 1.6-2.6] for total water and 1.5 L (1-1.7) for plain water, median urine volume was 1.9 L/24 h (IQR 1.6-2.4) and mean eUosm was 374 ± 104 mosm/L. Neither total water intake nor urine volume was associated with either kidney outcome. Kidney failure risk increased significantly with decreasing eUosm ˂292 mosm/L. Adjusted HRs (95% CIs) for kidney failure associated with plain water intake were 1.88 (1.02-3.47), 1.59 (1.06-2.38), 1.76 (0.95-3.24) and 1.55 (1.03-2.32) in patients drinking <0.5, 0.5-1.0, 1.5-2.0 and >2.0 L/day compared with those drinking 1.0-1.5 L/day. High plain water intake was also significantly associated with faster eGFR decline. CONCLUSIONS: In patients with CKD, the relation between plain water intake and progression to kidney failure appears to be U-shaped. Both low and high intake may not be beneficial in CKD.

Tumour-Derived Cell Lines and Their Potential for Therapy Prediction in Patients with Metastatic Colorectal Cancer.

The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding metastases of 10 CRC patients were compared. Cell line characteristics and chemosensitivity were investigated pairwise for primary and metastatic tumours of four patients. PDX models of one patient were treated in vivo for proof of concept. Driver mutations did not differ between primaries and metastases, while the latter accumulated additional mutations. In vitro chemosensitivity testing revealed no differences for responses to 5-FU and oxaliplatin between primary and metastatic cell lines. However, irinotecan response differed significantly: the majority of metastases-derived cell lines was less sensitive to irinotecan than their matching primary counterpart. Therapy recommendations based on these findings were compared to clinical treatment response and mostly in line with the predicted outcome. Therefore, primary tumour cell models seem to be a good tool for drug response testing and conclusion drawing for later metastases. With further data from tumour-derived cell models, such predictions could improve clinical treatment decisions, both recommending likely effective therapeutic options while excluding ineffective treatments.

Quality of Beverage Intake and Cardiometabolic and Kidney Outcomes: Insights From the STANISLAS Cohort.

Background and Aims: Beverages are an important aspect of diet, and their quality can possibly affect health. The Healthy Beverage Index (HBI) has been developed to take into account these effects. This study aimed to highlight the relationships between health and beverage quality by assessing the association of the HBI and its components with kidney and cardiometabolic (CM) outcomes in an initially healthy population-based familial cohort. Methods: This study included 1,271 participants from the STANISLAS cohort. The HBI, which includes 10 components of habitual beverage consumption, was calculated. Associations of the HBI and its components with estimated glomerular filtration rate (eGFR), albuminuria, hypertriglyceridemic waist (HTG waist), metabolic syndrome (MetS), carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and left ventricular mass (LV mass) were analyzed using multivariable linear or logistic regression models. Results: The median HBI score was 89.7 (78.6-95) out of 100 points. While the overall HBI score was not significantly associated with any of the studied outcomes, individual HBI components were found differently associated with the outcomes. cfPWV and cIMT were lower in participants who did not meet the full-fat milk criteria (p = 0.03 and 0.001, respectively). In men, higher cfPWV was observed for the "low Fat milk" (p = 0.06) and "alcohol" (p = 0.03) non-adherence criteria. Odds of HTG waist were higher with the non-adherence to sugar-sweetened beverages criteria (p < 0.001). eGFR was marginally higher with non-adherence to the coffee/tea criteria (p = 0.047). Conclusions: In this initially healthy population, HBI components were differently associated with kidney and cardiometabolic outcomes, despite a good overall HBI score. Our results highlight specific impacts of different beverage types and suggest that beverages could have an impact on kidney and cardiometabolic health.

Building a Reliable Health Care System: A Lean Six Sigma Quality Improvement Initiative on Patient Handoff.

BACKGROUND: There is limited evidence available identifying best practices to promote and sustain optimal outpatient-to-inpatient handoff processes to ensure safe and reliable continuity of care. LOCAL PROBLEM: A sentinel event occurred during the transition of care from the outpatient-to-inpatient setting. A root cause analysis revealed that the facility's standard operating procedure for patient handoffs was not consistently followed. METHODS: A Lean Six Sigma approach was used to improve patient transfer with the implementation of a Situation-Background-Assessment-Recommendation handoff policy. Inferential and statistical process control methods were used to assess performance outcomes pre- and postdissemination. RESULTS: Over 36 months there was a slow, steady decrease in patient transfer time including reduced variability. The most significant improvement effect occurred in the third year with a 50% reduction in transfer time. CONCLUSIONS: Longitudinal monitoring provides the opportunity to accurately identify beneficial outcomes, which develop downstream from initial quality improvement efforts.

APOBEC3A catalyzes mutation and drives carcinogenesis in vivo.

The APOBEC3 family of antiviral DNA cytosine deaminases is implicated as the second largest source of mutation in cancer. This mutational process may be a causal driver or inconsequential passenger to the overall tumor phenotype. We show that human APOBEC3A expression in murine colon and liver tissues increases tumorigenesis. All other APOBEC3 family members, including APOBEC3B, fail to promote liver tumor formation. Tumor DNA sequences from APOBEC3A-expressing animals display hallmark APOBEC signature mutations in TCA/T motifs. Bioinformatic comparisons of the observed APOBEC3A mutation signature in murine tumors, previously reported APOBEC3A and APOBEC3B mutation signatures in yeast, and reanalyzed APOBEC mutation signatures in human tumor datasets support cause-and-effect relationships for APOBEC3A-catalyzed deamination and mutagenesis in driving multiple human cancers.