Integrated Proteomic and Metabolomic Modules associated with Risk of Kidney Disease Progression.

BACKGROUND: Proteins and metabolites play crucial roles in various biological functions and are frequently interconnected through enzymatic or transport processes. METHODS: We present an integrated analysis of 4,091 proteins and 630 metabolites in the Chronic Renal Insufficiency Cohort Study (N=1,708; average follow-up for kidney failure [KF], 9.5 years, with 537 events). Proteins and metabolites were integrated using an unsupervised clustering method and we assessed associations between clusters and CKD progression and kidney failure using Cox proportional hazards models. Analyses were adjusted for demographics and risk factors including the estimated glomerular filtration rate (eGFR) and urine protein-creatinine ratio. Associations were identified in a discovery sample (random two-thirds, N=1139) and then evaluated in a replication sample (one-third, N=569). RESULTS: We identified 139 modules of correlated proteins and metabolites, which were represented by their principal components (PC). Modules and PC loadings were projected onto the replication sample which demonstrated a consistent network structure. Two modules, representing a total of 236 proteins and 82 metabolites, were robustly associated with both CKD progression and kidney failure in both discovery and validation samples. Using gene set enrichment, several transmembrane related terms were identified as over-represented in these modules. Transmembrane-ephrin receptor activity displayed the largest odds (OR = 13.2, P-value = 5.5×10 -5 ). A module containing CRIM1 and NPNT expressed in podocytes demonstrated particularly strong associations with kidney failure (P-value = 2.6×10 -5 ). CONCLUSIONS: This study demonstrates that integration of the proteome and metabolome can identify functions of pathophysiologic importance in kidney disease.

Proteomics of CKD progression in the chronic renal insufficiency cohort.

Progression of chronic kidney disease (CKD) portends myriad complications, including kidney failure. In this study, we analyze associations of 4638 plasma proteins among 3235 participants of the Chronic Renal Insufficiency Cohort Study with the primary outcome of 50% decline in estimated glomerular filtration rate or kidney failure over 10 years. We validate key findings in the Atherosclerosis Risk in the Communities study. We identify 100 circulating proteins that are associated with the primary outcome after multivariable adjustment, using a Bonferroni statistical threshold of significance. Individual protein associations and biological pathway analyses highlight the roles of bone morphogenetic proteins, ephrin signaling, and prothrombin activation. A 65-protein risk model for the primary outcome has excellent discrimination (C-statistic[95%CI] 0.862 [0.835, 0.889]), and 14/65 proteins are druggable targets. Potentially causal associations for five proteins, to our knowledge not previously reported, are supported by Mendelian randomization: EGFL9, LRP-11, MXRA7, IL-1 sRII and ILT-2. Modifiable protein risk markers can guide therapeutic drug development aimed at slowing CKD progression.

Potential Impact of the COVID-19 Pandemic on Public Perception of Water Pipes on Reddit: Observational Study.

Background: Socializing is one of the main motivations for water pipe smoking. Restrictions on social gatherings during the COVID-19 pandemic might have influenced water pipe smokers' behaviors. As one of the most popular social media platforms, Reddit has been used to study public opinions and user experiences. Objective: In this study, we aimed to examine the influence of the COVID-19 pandemic on public perception and discussion of water pipe tobacco smoking using Reddit data. Methods: We collected Reddit posts between December 1, 2018, and June 30, 2021, from a Reddit archive (PushShift) using keywords such as "waterpipe," "hookah," and "shisha." We examined the temporal trend in Reddit posts mentioning water pipes and different locations (such as homes and lounges or bars). The temporal trend was further tested using interrupted time series analysis. Sentiment analysis was performed to study the change in sentiment of water pipe-related posts before and during the pandemic. Topic modeling using latent Dirichlet allocation (LDA) was used to examine major topics discussed in water pipe-related posts before and during the pandemic. Results: A total of 45,765 nonpromotion water pipe-related Reddit posts were collected and used for data analysis. We found that the weekly number of Reddit posts mentioning water pipes significantly increased at the beginning of the COVID-19 pandemic (P<.001), and gradually decreased afterward (P<.001). In contrast, Reddit posts mentioning water pipes and lounges or bars showed an opposite trend. Compared to the period before the COVID-19 pandemic, the average number of Reddit posts mentioning lounges or bars was lower at the beginning of the pandemic but gradually increased afterward, while the average number of Reddit posts mentioning the word "home" remained similar during the COVID-19 pandemic (P=.29). While water pipe-related posts with a positive sentiment were dominant (12,526/21,182, 59.14% before the pandemic; 14,686/24,583, 59.74% after the pandemic), there was no change in the proportion of water pipe-related posts with different sentiments before and during the pandemic (P=.19, P=.26, and P=.65 for positive, negative, and neutral posts, respectively). Most topics related to water pipes on Reddit were similar before and during the pandemic. There were more discussions about the opening and closing of hookah lounges or bars during the pandemic. Conclusions: This study provides a first evaluation of the possible impact of the COVID-19 pandemic on public perceptions of and discussions about water pipes on Reddit.

Proteomic cardiovascular risk assessment in chronic kidney disease.

AIMS: Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models. METHODS AND RESULTS: Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis. CONCLUSION: In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population.

Testican-2 Is Associated with Reduced Risk of Incident ESKD.

BACKGROUND: Testican-2 was recently identified as a podocyte-derived protein that is released into circulation by the kidneys and is positively correlated with eGFR and eGFR slope. However, whether higher testican-2 levels are associated with lower risk of ESKD is unknown. METHODS: Aptamer-based proteomics assessed blood testican-2 levels among participants in the African American Study of Kidney Disease and Hypertension (AASK, n =703), the Chronic Renal Insufficiency Cohort (CRIC) study ( n =3196), and the Atherosclerosis Risk in Communities (ARIC) study ( n =4378). We compared baseline characteristics by testican-2 tertile and used Cox proportional hazards models to study the association of testican-2 with incident ESKD. RESULTS: Higher testican-2 levels were associated with higher measured GFR (mGFR) in AASK, higher eGFR in the CRIC and ARIC studies, and lower albuminuria in all cohorts. Baseline testican-2 levels were significantly associated with incident ESKD in Cox proportional hazards models adjusted for age, sex, and race (model 1) and model 1+mGFR or eGFR+comorbidities (model 2). In model 3 (model 2+proteinuria), the associations between testican-2 (per SD increase) and incident ESKD were AASK (hazard ratio [HR]=0.84 [0.72 to 0.98], P =0.023), CRIC (HR=0.95 [0.89 to 1.02], P =0.14), ARIC (HR=0.54 [0.36 to 0.83], P =0.0044), and meta-analysis (HR=0.92 [0.86 to 0.98], P =0.0073). CONCLUSIONS: Across three cohorts spanning >8000 individuals, testican-2 is associated with kidney health and prognosis, with higher levels associated with reduced risk of ESKD.

Misinformation versus Facts: Understanding the Influence of News regarding COVID-19 Vaccines on Vaccine Uptake.

Background: There is a lot of fact-based information and misinformation in the online discourses and discussions about the COVID-19 vaccines. Method: Using a sample of nearly four million geotagged English tweets and the data from the CDC COVID Data Tracker, we conducted the Fama-MacBeth regression with the Newey-West adjustment to understand the influence of both misinformation and fact-based news on Twitter on the COVID-19 vaccine uptake in the US from April 19 when US adults were vaccine eligible to June 30, 2021, after controlling state-level factors such as demographics, education, and the pandemic severity. We identified the tweets related to either misinformation or fact-based news by analyzing the URLs. Results: One percent increase in fact-related Twitter users is associated with an approximately 0.87 decrease (B = -0.87, SE = 0.25, and p < .001) in the number of daily new vaccinated people per hundred. No significant relationship was found between the percentage of fake-news-related users and the vaccination rate. Conclusion: The negative association between the percentage of fact-related users and the vaccination rate might be due to a combination of a larger user-level influence and the negative impact of online social endorsement on vaccination intent.

Early Clinical Outcomes of Thoracoscopic Mitral Valvuloplasty: The First 90 Cases.

BACKGROUND: We reported 90 cases of thoracoscopic mitral valvuloplasty in its early stages and sought to analyze early clinical outcomes. METHODS: Ninety consecutive patients, who underwent thoracoscopic mitral valvuloplasty at our institute between April 2020 and December 2021, were assessed for outcomes. Clinical data, including baseline characteristics, operative data, postoperative data, and early follow-up results, were collected. The early clinical outcomes were used to assess the reliability and efficiency of this technique. RESULTS: No in-hospital death occurred. One patient underwent a median sternotomy for bleeding. Intraoperative transesophageal echocardiography revealed no mitral regurgitation in 82 patients and mitral regurgitation of 0-2 cm2 in six. The remaining two patients with mitral regurgitation >2 cm2 experienced serious systolic anterior motion but underwent successful re-valvuloplasty during a second pump-up. the mean cardiopulmonary bypass time was 177.1±54.8 min and aortic clamping time, 114.0±44.9 min. Each patient received a prosthetic ring (CG Future™), and 64 patients received artificial chordae with an average of 2.7±1.5 (ranging from 1 to 6) pairs. The mean follow up was 8.8±7.0 (range, 1-22 months), while two patients were lost to follow up. Recurrent severe mitral regurgitation was observed in one patient three months after the operation, and mitral valve replacement was performed via median sternotomy. During follow up, one patient died of upper respiratory tract infection, and one suffered from low cardiac output. CONCLUSIONS: Thoracoscopic mitral valvuloplasty is safe and effective and, once surgeons overcome the learning curve, can achieve excellent early clinical outcomes.

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study.

BACKGROUNDMetabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.METHODSWe examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study.RESULTSIn CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.CONCLUSIONOur findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.FUNDINGThis study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).

Discussion of waterpipe tobacco smoking on reddit.

Objectives: This study aimed to examine public discussions of waterpipe tobacco smoking, as well as the potential associations of different waterpipe flavors with health symptoms, using Reddit data. Study design: This is an observational infodemiology study. Methods: Using keywords such as "waterpipe", "hookah", and "shisha", Reddit posts were extracted from Reddit Archive (pushshift.io) between February 1, 2016, and December 31, 2020. Temporal analysis was used to understand the longitudinal trend of the discussions about waterpipe tobacco smoking. Topic modeling using the Latent Dirichlet Allocation (LDA) model was performed to examine the topics on waterpipe tobacco. We estimated the conditional probability of having each health problem for each given waterpipe flavor. Results: The discussion of waterpipe on Reddit was slowly decreasing from 2016 to 2018 and surged until May 2020. The fruit was the most popular waterpipe flavor and the neurological symptom was the most mentioned health category in waterpipe-related Reddit posts. The most popular topics included "Friends spending time together at night with waterpipe smoking", "Playing games and smoking waterpipe at a hookah bar", and "Discussing waterpipe flavors and related products". Some waterpipe flavors were more associated with certain health problems than others. For example, mint/menthol flavor had a high probability to be associated with symptoms related to throat and mouth. Conclusion: This study provided longitudinal surveillance of waterpipe tobacco smoking discussed on Reddit. We showed the potential relationship between waterpipe flavors and health symptoms, which provides preliminary evidence about the potential health effects of waterpipe tobacco smoking.

Plasma Biomarkers as Risk Factors for Incident CKD.

Introduction: Earlier identification of individuals at high risk of chronic kidney disease (CKD) may facilitate improved risk factor mitigation. Methods: We evaluated the association of novel plasma biomarkers with incident CKD using a case-cohort design in participants without diabetes and with baseline estimated glomerular filtration rate (eGFR) ≥ 60 ml/min per 1.73 m2 in the Multi-Ethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohorts. Incident CKD was defined as development of eGFR < 60 ml/min per 1.73 m2 and ≥40% decline in eGFR from baseline. We measured plasma markers of inflammation/fibrosis-soluble tumor necrosis factor receptors (TNFRs) 1 and 2 (TNFR-1 and TNFR-2), monocyte chemotactic protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble urokinase-type plasminogen activator receptor (suPAR)-and tubular injury (kidney injury molecule 1 [KIM-1]). Cox regression models weighted for the case-cohort design were used to estimate hazard ratios (HRs) of incident CKD after adjustment for CKD risk factors, eGFR, and albuminuria. Results: In MESA (median follow-up of 9.2 years), there were 497 individuals in the random subcohort and 163 incident CKD cases. In REGARDS (median follow-up of 9.4 years), there were 497 individuals in the random subcohort and 497 incident CKD cases. Each 2-fold higher plasma KIM-1 (adjusted HR 1.38 [95% CI 1.05-1.81]), suPAR (1.96 [1.10-3.49]), TNFR-1 (1.65 [1.04-2.62]), TNFR-2 (2.02 [1.21-3.38]), and YKL-40 (1.38 [1.09-1.75]) concentrations were associated with incident CKD in MESA. In REGARDS, TNFR-1 (1.99 [1.43-2.76]) and TNFR-2 (1.76 [1.22-2.54]) were associated with incident CKD. Conclusion: Plasma concentrations of soluble TNFR-1 and TNFR-2 are consistently associated with incident CKD in nondiabetic community-living individuals in MESA and REGARDS.

Trans-ethnic genome-wide association study of blood metabolites in the Chronic Renal Insufficiency Cohort (CRIC) study.

Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m2 in the White and Black participants, respectively. There were 45 significant metabolite associations at 19 loci, including novel associations at PYROXD2, PHYHD1, FADS1-3, ACOT2, MYRF, FAAH, and LIPC. The strength of associations was unchanged in models additionally adjusted for estimated glomerular filtration rate and proteinuria, consistent with a direct biochemical effect of gene products on associated metabolites. At several loci, trans-ethnic meta-analysis, which leverages differences in linkage disequilibrium across populations, reduced the number and/or genomic interval spanned by potentially causal single nucleotide polymorphisms compared to fine-mapping in the White participant cohort alone. Across all validated associations, we found strong concordance in effect sizes of the potentially causal single nucleotide polymorphisms between White and Black study participants. Thus, our study identifies novel genetic determinants of blood metabolites in chronic kidney disease, demonstrates the value of diverse cohorts to improve causal inference in metabolomics GWAS, and underscores the shared genetic basis of metabolism across race.

Time-Updated Changes in Estimated GFR and Proteinuria and Major Adverse Cardiac Events: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Evaluating repeated measures of estimated glomerular filtration rate (eGFR) and urinary protein-creatinine ratio (UPCR) over time may enhance our ability to understand the association between changes in kidney parameters and cardiovascular disease risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Annual visit data from 2,438 participants in the Chronic Renal Insufficiency Cohort (CRIC). EXPOSURES: Average and slope of eGFR and UPCR in time-updated, 1-year exposure windows. OUTCOMES: Incident heart failure, atherosclerotic cardiovascular disease events, death, and a composite of incident heart failure, atherosclerotic cardiovascular disease events, and death. ANALYTICAL APPROACH: A landmark analysis, a dynamic approach to survival modeling that leverages longitudinal, iterative profiles of laboratory and clinical information to assess the time-updated 3-year risk of adverse cardiovascular outcomes. RESULTS: Adjusting for baseline and time-updated covariates, every standard deviation lower mean eGFR (19mL/min/1.73m2) and declining slope of eGFR (8mL/min/1.73m2 per year) were independently associated with higher risks of heart failure (hazard ratios [HRs] of 1.82 [95% CI, 1.39-2.44] and 1.28 [95% CI, 1.12-1.45], respectively) and the composite outcome (HRs of 1.32 [95% CI, 1.11-1.54] and 1.11 [95% CI, 1.03-1.20], respectively). Every standard deviation higher mean UPCR (136mg/g) and increasing UPCR (240mg/g per year) were also independently associated with higher risks of heart failure (HRs of 1.58 [95% CI, 1.28-1.97] and 1.20 [95% CI, 1.10-1.29], respectively) and the composite outcome (HRs of 1.33 [95% CI, 1.17-1.50] and 1.12 [95% CI, 1.06-1.18], respectively). LIMITATIONS: Limited generalizability of annual eGFR and UPCR assessments; several biomarkers for cardiovascular disease risk were not available annually. CONCLUSIONS: Using the landmark approach to account for time-updated patterns of kidney function, average and slope of eGFR and proteinuria were independently associated with 3-year cardiovascular risk. Short-term changes in kidney function provide information about cardiovascular risk incremental to level of kidney function, representing possible opportunities for more effective management of patients with chronic kidney disease.

Reported practice patterns in the ambulatory care setting for patients with CHD.

INTRODUCTION: In the absence of evidence-based guidelines, paediatric cardiologists monitor patients in the ambulatory care setting largely according to personal, patient, institutional, and/or financial dictates, all of which likely contribute to practice variability. Minimising practice variability may optimise quality of care while incurring lower costs. We sought to describe self-reported practice patterns and physician attitudes about factors influencing their testing strategies using vignettes describing common scenarios in the care of asymptomatic patients with tetralogy of Fallot and d-transposition of the great arteries. METHODS: We conducted a cross-sectional survey of paediatric cardiologists attending a Continuing Medical Educational conference and at our centre. The survey elicited physician characteristics, self-reported testing strategies, and reactions to factors that might influence their decision to order an echocardiogram. RESULTS: Of 267 eligible paediatric cardiologists, 110 completed the survey. The majority reported performing an annual physical examination (66-82%), electrocardiogram (74-79%), and echocardiogram (56-76%) regardless of patient age or severity of disease. Other tests (i.e. Holter monitors, exercise stress tests or cardiac MRIs) were ordered less frequently and less consistently. We observed within physician consistency in frequency of test ordering. In vignettes of younger children with mild disease, higher frequency testers were younger than lower frequency testers. CONCLUSIONS: These results suggest potential practice pattern variability, which needs to be further explored in real-life settings. If clinical outcomes for patients followed by low frequency testers match that of high frequency testers, then room to modify practice patterns and lower costs without compromising quality of care may exist.

Proteins Associated with Risk of Kidney Function Decline in the General Population.

BACKGROUND: Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD. METHODS: We quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate <5%) in both time periods in 3249 participants in the Chronic Renal Insufficiency Cohort (CRIC) and 703 participants in the African American Study of Kidney Disease and Hypertension (AASK). We also compared the genetic determinants of protein levels with those from a meta-analysis genome-wide association study of eGFR. RESULTS: In models adjusted for multiple covariates, including baseline eGFR and albuminuria, we identified 13 distinct proteins that were significantly associated with the composite end point in both time periods, including TNF receptor superfamily members 1A and 1B, trefoil factor 3, and ß-trace protein. Of these proteins, 12 were also significantly associated in CRIC, and nine were significantly associated in AASK. Higher levels of each protein associated with higher risk of 50% eGFR decline or ESKD. We found genetic evidence for a causal role for one protein, lectin mannose-binding 2 protein (LMAN2). CONCLUSIONS: Large-scale proteomic analysis identified both known and novel proteomic risk factors for eGFR decline.

Plasma Metabolomic Signatures of Healthy Dietary Patterns in the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: In individuals with chronic kidney disease (CKD), healthy dietary patterns are inversely associated with CKD progression. Metabolomics, an approach that measures many small molecules in biofluids, can identify biomarkers of healthy dietary patterns. OBJECTIVES: We aimed to identify known metabolites associated with greater adherence to 4 healthy dietary patterns in CKD patients. METHODS: We examined associations between 486 known plasma metabolites and Healthy Eating Index (HEI)-2015, Alternative Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension (DASH) diet, and alternate Mediterranean diet (aMED) in 1056 participants (aged 21-74 y at baseline) in the Chronic Renal Insufficiency Cohort (CRIC) Study. Usual dietary intake was assessed using a semiquantitative FFQ. We conducted multivariable linear regression models to study associations between healthy dietary patterns and individual plasma metabolites, adjusting for sociodemographic characteristics, health behaviors, and clinical factors. We used principal component analysis to identify groups of metabolites associated with individual food components within healthy dietary patterns. RESULTS: After Bonferroni correction, we identified 266 statistically significant diet-metabolite associations (HEI: n = 60; AHEI: n = 78; DASH: n = 77; aMED: n = 51); 78 metabolites were associated with >1 dietary pattern. Lipids with a longer acyl chain length and double bonds (unsaturated) were positively associated with all 4 dietary patterns. A metabolite pattern low in saturated diacylglycerols and triacylglycerols, and a pattern high in unsaturated triacylglycerols was positively associated with intake of healthy food components. Plasmalogens were negatively associated with the consumption of nuts and legumes and healthy fat, and positively associated with the intake of red and processed meat. CONCLUSIONS: We identified many metabolites associated with healthy dietary patterns, indicative of food consumption. If replicated, these metabolites may be considered biomarkers of healthy dietary patterns in patients with CKD.

Totally endoscopic mitral valve surgery: early experience in 188 patients.

INTRODUCTION: Totally endoscopic technique has been widely used in cardiac surgery, and minimally invasive totally endoscopic mitral valve surgery has been developed as an alternative to median sternotomy for many patients with mitral valve disease. In this study, we describe our experience about a modified minimally invasive totally endoscopic mitral valve surgery and reported the preliminary results of totally endoscopic mitral valve surgery. The aim of this retrospective study is to evaluate the results of totally endoscopic technique in mitral valve surgery. MATERIAL AND METHODS: We retrospectively reviewed the profiles of 188 patients who were treated for mitral valve disease by modified totally endoscopic mitral valve surgery at our institution between January 2019 and December 2020. The procedure was performed under endoscopic right minithoracotomy and with femoro-femoral cannulation using the single two-stage venous cannula. RESULTS: A total of 188 patients underwent total endoscopic mitral valve surgery. Fifty-six patients had concomitant tricuspid valvuloplasty, 11 patients underwent concomitant ablation of atrial fibrillation and atrial septal defect repair was performed in three patients. Only one patient postoperatively died of multi-organ failure. Two patients were converted to median sternotomy. Except for one patient underwent operation to stop the bleeding from the incision site, no other serious complications nor reintervention occurred during the follow-up period. CONCLUSIONS: The modified totally endoscopic mitral valve surgery performed at our institution is technically feasible and safe with the same efficacy as reported studies.

Subtyping CKD Patients by Consensus Clustering: The Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: CKD is a heterogeneous condition with multiple underlying causes, risk factors, and outcomes. Subtyping CKD with multidimensional patient data holds the key to precision medicine. Consensus clustering may reveal CKD subgroups with different risk profiles of adverse outcomes. METHODS: We used unsupervised consensus clustering on 72 baseline characteristics among 2696 participants in the prospective Chronic Renal Insufficiency Cohort (CRIC) study to identify novel CKD subgroups that best represent the data pattern. Calculation of the standardized difference of each parameter used the cutoff of ±0.3 to show subgroup features. CKD subgroup associations were examined with the clinical end points of kidney failure, the composite outcome of cardiovascular diseases, and death. RESULTS: The algorithm revealed three unique CKD subgroups that best represented patients' baseline characteristics. Patients with relatively favorable levels of bone density and cardiac and kidney function markers, with lower prevalence of diabetes and obesity, and who used fewer medications formed cluster 1 (n=1203). Patients with higher prevalence of diabetes and obesity and who used more medications formed cluster 2 (n=1098). Patients with less favorable levels of bone mineral density, poor cardiac and kidney function markers, and inflammation delineated cluster 3 (n=395). These three subgroups, when linked with future clinical end points, were associated with different risks of CKD progression, cardiovascular disease, and death. Furthermore, patient heterogeneity among predefined subgroups with similar baseline kidney function emerged. CONCLUSIONS: Consensus clustering synthesized the patterns of baseline clinical and laboratory measures and revealed distinct CKD subgroups, which were associated with markedly different risks of important clinical outcomes. Further examination of patient subgroups and associated biomarkers may provide next steps toward precision medicine.

All-Cause and Cardiovascular Disease Mortality Among Breast Cancer Survivors in CLUE II, a Long-Standing Community-Based Cohort.

BACKGROUND: There is growing evidence that breast cancer survivors have higher cardiovascular disease (CVD) mortality relative to the general population. Information on temporal patterns for all-cause and CVD mortality among breast cancer survivors relative to cancer-free women is limited. METHODS: All-cause and CVD-related mortality were compared in 628 women with breast cancer and 3140 age-matched cancer-free women within CLUE II, a prospective cohort. We calculated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression for all-cause mortality, and Fine and Gray models for CVD-related mortality to account for competing risks. RESULTS: Over 25 years of follow-up, 916 deaths occurred (249 CVD related). Breast cancer survivors had an overall higher risk of dying compared with cancer-free women (HR = 1.79, 95% CI = 1.53 to 2.09) irrespective of time since diagnosis, tumor stage, estrogen receptor status, and older age at diagnosis (≥70 years). Risk of death was greatest among older survivors at more than 15 years after diagnosis (HR = 2.69, 95% CI = 1.59 to 4.55). CVD (69.1% ischemic heart disease) was the leading cause of death among cancer-free women and the second among survivors. Survivors had an increase in CVD-related deaths compared with cancer-free women beginning at 8 years after diagnosis (HR = 1.65, 95% CI = 1.00 to 2.73), with the highest risk among older survivors (HR = 2.24, 95% CI = 1.29 to 3.88) and after estrogen receptor-positive disease (HR = 1.85, 95% CI = 1.06 to 3.20). CONCLUSIONS: Breast cancer survivors continue to have an elevated mortality compared with the general population for many years after diagnosis. Preventing cardiac deaths, particularly among older breast cancer patients, could lead to reductions in mortality.

NAT8 Variants, N-Acetylated Amino Acids, and Progression of CKD.

BACKGROUND AND OBJECTIVES: Genetic variants in NAT8, a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two NAT8-associated metabolites, N-δ-acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in NAT8, N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; n=962), the Atherosclerosis Risk in Communities (ARIC) study (n=1050), and BioMe, an electronic health record-linked biorepository (n=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (n=1624). RESULTS: Of 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (P<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N-δ-acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure, after adjustment for confounders and combining results in meta-analysis (combined hazard ratios per two-fold higher amino acid levels: 1.48, 1.44, 1.21, 1.65, and 1.41, respectively; 95% confidence intervals: 1.21 to 1.81, 1.22 to 1.70, 1.08 to 1.37, 1.29 to 2.10, and 1.17 to 1.71, respectively; all P values <0.05/14). None of the urinary levels of these N-acetylated amino acids were associated with kidney failure in the GCKD study. CONCLUSIONS: We demonstrate significant associations between an NAT8 gene variant and 14 N-acetylated amino acids, five of which had circulation levels that were associated with kidney failure.