AutoGDC: A Python Package for DNA Methylation and Transcription Meta-Analyses.

Motivation: 0.1The Genomic Data Commons is a powerful resource which facilitates the exploration of molecular alterations across various diseases. However, utilizing this resource for meta-analysis requires many different tools to query, download, organize, and analyze the data. In order to facilitate a more rapid, simple means of analyzing DNA methylation and RNA sequencing datasets from the GDC we developed autogdc, a python package that integrates data curation and preprocessing with meta-analysis functionality into one simplified bioinformatic pipeline. Availability and Implementation: 0.2The autogdc python package is available under the GPLv3 license at along with several examples of typical use-case scenarios in the form of a jupyter notebook. The data is all originally provided by the GDC, and is therefore available under the NIH Genomic Data Sharing (GDS) and NCI GDS policies.

Testing clinical selection criteria for intraoperative transoesophageal echocardiography in isolated coronary artery bypass graft surgery.

Background: There is a lack of evidence associating intraoperative transoesophageal echocardiography (TOE) use with improved outcomes among coronary artery bypass graft (CABG) surgery subpopulations. Methods: This matched retrospective cohort study used a US private claims dataset to compare outcomes among different CABG surgery patient populations with vs without TOE. Statistical analyses involved exact matching on pre-selected subgroups (congestive heart failure, single vessel, and multivessel CABG) and used fine and propensity-score balanced techniques to conduct multiple matched comparisons and sensitivity analyses. Results: Of 42 249 patients undergoing isolated CABG surgery, 24 919 (59.0%) received and 17 330 (41.0%) did not receive TOE. After matching, intraoperative TOE was significantly associated with a lower, 30-day mortality: 2.63% vs 3.20% (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.71-0.92; P=0.002). In the subgroup matched comparisons, intraoperative TOE was significantly associated with a lower, 30-day mortality rate among those with congestive heart failure: 4.20% vs 5.26% (OR: 0.78; 95% CI: 0.66-0.94; P=0.007) and among those undergoing multivessel CABG with congestive heart failure: 4.23% vs 5.24% (OR: 0.80; 95% CI: 0.65-0.97; P=0.025), but not among those undergoing multivessel CABG without congestive heart failure: 1.83% vs 2.15% (OR: 0.85; 95% CI: 0.70-1.02; P=0.089, nor any of the remaining three subgroups. Conclusions: Among US adults undergoing isolated CABG surgery, intraoperative TOE was associated with improved outcomes in patients with congestive heart failure (vs without) and among patients undergoing multivessel (vs single vessel) CABG. These findings support prioritised TOE allocation to these patient populations at centres with limited TOE capabilities.

BioVDB: biological vector database for high-throughput gene expression meta-analysis.

High-throughput sequencing has created an exponential increase in the amount of gene expression data, much of which is freely, publicly available in repositories such as NCBI's Gene Expression Omnibus (GEO). Querying this data for patterns such as similarity and distance, however, becomes increasingly challenging as the total amount of data increases. Furthermore, vectorization of the data is commonly required in Artificial Intelligence and Machine Learning (AI/ML) approaches. We present BioVDB, a vector database for storage and analysis of gene expression data, which enhances the potential for integrating biological studies with AI/ML tools. We used a previously developed approach called Automatic Label Extraction (ALE) to extract sample labels from metadata, including age, sex, and tissue/cell-line. BioVDB stores 438,562 samples from eight microarray GEO platforms. We show that it allows for efficient querying of data using similarity search, which can also be useful for identifying and inferring missing labels of samples, and for rapid similarity analysis.

Standing on the shoulders of a giant: The legacy of Robert M. Sellers.

Robert M. Sellers, PhD, most known for his influential and highly cited Multidimensional Model of Racial Identity (MMRI), is one of the most prolific and foundational Black scholars in psychology. From racial identity theory development and measurement to conceptual and methodological innovations in studying the lived experiences of Black people, Sellers' scholarship centers on the lives of Black communities. Sellers' mentorship and contributions to the professional development of scholars and professionals of color have supported and catalyzed new intergenerational knowledge building by these scholars, ensuring a perpetuating and far-reaching legacy in psychology. In this article, we: (a) celebrate Sellers' enduring contribution to the racial identity literature and its profound impact on psychology as a discipline as well as numerous subfields of psychology, (b) outline his contributions to the racial socialization literature, (c) describe methodological innovations in racial identity and racial socialization research advanced through his scholarship, and (d) summarize his contributions in professional development and mentorship and his leadership roles. Sellers' scholarly contributions and mentorship have transformed the discipline of psychology and the social sciences broadly speaking, making him one of the most influential psychologists in the modern era. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor ß1 (TGFß1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

Risk of Stroke and Major Bleeding With Vitamin K Antagonist Use After Mitral Valve Repair.

BACKGROUND: Guidelines are discordant on the use of a vitamin K antagonist (VKA) after mitral valve repair (MVr) to reduce the risk of cerebral embolic events. We performed an observational study among patients who underwent a MVr, without perioperative atrial fibrillation, to determine the risk of cerebral ischemic and major bleeding events with or without VKA. METHODS: From 2004 to 2016, we included patients who underwent MVr, using a national administrative claims database. Those with preoperative atrial fibrillation and anticoagulant use were excluded. Patients were stratified based on the presence of a VKA. Inverse probability weighting with a Cox proportional hazard model was used. RESULTS: After MVr, 754 patients were discharged on VKA and 1462 on no-VKA. We found no difference in the cumulative incidence for embolic stroke at 180 days (VKA: 2.21% vs no-VKA: 1.50%; hazard ratio, 1.35; P = .38). However, VKA patients had a significantly increased risk for any-cause major bleeding events at 180 days (VKA: 8.58% vs no-VKA: 4.21%; hazard ratio, 2.09; P < .001). VKA patients also had increased need for a pericardiocentesis/pericardial window at 30 days after discharge (VKA: 1.13% vs no-VKA: 0.37%; hazard ratio, 3.88; P = .025). CONCLUSIONS: Our study suggests that VKA after MVr does not reduce the risk of cerebral embolic events but is associated with an increased risk of major bleeding events.

Methylation Array Signals are Predictive of Chronological Age Without Bisulfite Conversion.

DNA methylation data has been used to make "epigenetic clocks" which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. Here, we demonstrate how another hallmark of aging, genomic instability, influences methylation measurements in both bisulfite sequencing and methylation arrays. We found that non-methylation factors lead to "pseudomethylation" signals that are both confounding of epigenetic clocks and uniquely age predictive. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.

Multi-tissue DNA methylation microarray signature is predictive of gene function.

Background Transcriptional correlation networks derived from publicly available gene expression microarrays have been previously shown to be predictive of known gene functions, but less is known about the predictive capacity of correlated DNA methylation at CpG sites. Guilt-by-association co-expression methods can adapted for use with DNA methylation when a representative methylation value is created for each gene. We examine how methylation compares to expression in predicting Gene Ontology terms using both co-methylation and traditional machine learning approaches across different types of representative methylation values per gene. Methods We perform guilt-by-association gene function prediction with a suite of models called Methylation Array Network Analysis, using a network of correlated methylation values derived from over 24,000 samples. In generating the correlation matrix, the performance of different methods of collapsing probe-level data effect on the resulting gene function predictions was compared, along with the use of different regions surrounding the gene of interest. Results Using mean comethylation of a given gene to its annotated term had an overall highest prediction macro-AUC of 0.60 using mean gene body methylation, across all Gene Ontology terms. This was increased using the logistic regression approach with the highest macro-AUC of 0.82 using mean gene body methylation, compared to the naive predictor of 0.72. Conclusion Genes correlated in their methylation state are functionally related. Genes clustered in co-methylation space were enriched for chromatin state, PRC2, immune response, and development-related terms.

Volume of frail patients predicts outcome in frail patients after cardiac surgery.

OBJECTIVE: Recent data from major noncardiac surgery suggest that outcomes in frail patients are better predicted by a hospital's volume of frail patients specifically, rather than overall surgical volume. We sought to evaluate this "frailty volume-frailty outcome relationship" in patients undergoing cardiac surgery. METHODS: We studied 72,818 frail patients undergoing coronary artery bypass grafting or valve replacement surgery from 2010 to 2014 using the Nationwide Readmissions Database. Frailty was defined using the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnoses indicator. Multilevel logistic regression was used to assess the independent effect of frailty volume by quartile on mortality, surgical complications, failure to rescue, nonhome discharge, 30-day readmissions, length of stay, and hospital costs in frail patients. RESULTS: In comparing the highest volume quartiles with the lowest, both overall cardiac surgical volume and volume for frail patients were significantly associated with shorter length of stay and reduced costs. However, frailty volume was also independently associated with significantly reduced in-hospital mortality (odds ratio, 0.79; 95% confidence interval, 0.67-0.94; P = .006) and failure to rescue (odds ratio, 0.83; 95% confidence interval, 0.70-0.98; P = .03), whereas no such association was seen between overall volume and either mortality (odds ratio, 0.94; 95% confidence interval, 0.74-1.10; P = .43) or failure to rescue (odds ratio, 0.98; 95% confidence interval, 0.83-1.17; P = .85). Neither frailty volume nor overall volume showed any significant relationship with the rate of 30-day readmissions. CONCLUSIONS: In frail patients undergoing cardiac surgery, surgical volume of frail patients was a significant independent of predictor of in-hospital mortality and failure to rescue, whereas overall surgical volume was not. Thus, the "frailty volume-outcome relationship" superseded the traditional "volume-outcome relationship" in frail patients with cardiac disease.

Viral Racism via Videos: A Study of Asians' Experiences of Interpersonal Discrimination Because of COVID-19.

This study analyzes five publicly posted videos wherein Asians experience interpersonal discrimination because of COVID-19. We think social scientists ignore how videos provide data for investigating interpersonal discrimination. We characterize the videos according to multiple features including context, characteristics, and responses of individuals involved, type of threat or mistreatment, and level of psychological and physical harm. We then summarize features across the videos. Among other things, analyses uncover implicit, explicit, and historically specific anti-Asian sentiment alongside evidence perpetrators are men and bystanders do not intervene typically. The Discussion contrasts Asians' experiences of interpersonal discrimination because of COVID-19 against the interpersonal and institutional discrimination faced by American Indians, blacks, and Hispanics in the United States. That contrast brings Asians' positionality into sharp relief.

Persistent Opioid Use After Cardiac Implantable Electronic Device Procedures.

BACKGROUND: Prescription opioids are a major contributor to the ongoing epidemic of persistent opioid use (POU). The incidence of POU among opioid-naïve patients after cardiac implantable electronic device (CIED) procedures is unknown. METHODS: This retrospective cohort study used data from a national administrative claims database from 2004 to 2018 of patients undergoing CIED procedures. Adult patients were included if they were opioid-naïve during the 180-day period before the procedure and did not undergo another procedure with anesthesia in the next 180 days. POU was defined by filling an additional opioid prescription >30 days after the CIED procedure. RESULTS: Of the 143 400 patients who met the inclusion criteria, 15 316 (11%) filled an opioid prescription within 14 days of surgery. Among these patients, POU occurred in 1901 (12.4%) patients 30 to 180 days after surgery. The likelihood of developing POU was increased for patients who had a history of drug abuse (odds ratio, 1.52; P=0.005), preoperative muscle relaxant (odds ratio, 1.52; P<0.001) or benzodiazepine (odds ratio, 1.23; P=0.001) use, or opioid use in the previous 5 years (OR, 1.76; P<0.0001). POU did not differ after subcutaneous implantable cardioverter defibrillator or other CIED procedures (11.1 versus 12.4%; P=0.5). In a sensitivity analysis excluding high-risk patients who were discharged to a facility or who had a history of drug abuse or previous opioid, benzodiazepine, or muscle relaxant use, 8.9% of the remaining cohort had POU. Patients prescribed >135 mg of oral morphine equivalents had a significantly increased risk of POU. CONCLUSIONS: POU is common after CIED procedures, and 12% of patients continued to use opioids >30 days after surgery. Higher initially prescribed oral morphine equivalent doses were associated with developing POU.

Many chronological aging clocks can be found throughout the epigenome: Implications for quantifying biological aging.

Epigenetic alterations are a hallmark of aging and age-related diseases. Computational models using DNA methylation data can create "epigenetic clocks" which are proposed to reflect "biological" aging. Thus, it is important to understand the relationship between predictive clock sites and aging biology. To do this, we examined over 450,000 methylation sites from 9,699 samples. We found ~20% of the measured genomic cytosines can be used to make many different epigenetic clocks whose age prediction performance surpasses that of telomere length. Of these predictive sites, the average methylation change over a lifetime was small (~1.5%) and these sites were under-represented in canonical regions of epigenetic regulation. There was only a weak association between "accelerated" epigenetic aging and disease. We also compare tissue-specific and pan-tissue clock performance. This is critical to applying clocks both to new sample sets in basic research, as well as understanding if clinically available tissues will be feasible samples to evaluate "epigenetic aging" in unavailable tissues (e.g., brain). Despite the reproducible and accurate age predictions from DNA methylation data, these findings suggest they may have limited utility as currently designed in understanding the molecular biology of aging and may not be suitable as surrogate endpoints in studies of anti-aging interventions. Purpose-built clocks for specific tissues age ranges or phenotypes may perform better for their specific purpose. However, if purpose-built clocks are necessary for meaningful predictions, then the utility of clocks and their application in the field needs to be considered in that context.

Cardiac surgery simulation - Part 3: Coronary anastomosis.

Our group has previously described how dedicated practice outside the operating room can improve surgical technique and enhance intraoperative performance. We have also recently developed a "do-it-yourself" simulator made from inexpensive, easily obtainable materials to practice a variety of operative scenarios in cardiac surgery. This video tutorial demonstrates our Coronary Anastomosis Module, which is designed for practice of both distal and proximal coronary anastomoses.

The impact of surgeon and hospital procedural volume on outcomes after aortic root replacement in the United States.

OBJECTIVE: Surgeon procedural volume for complex cardiac procedures have become important quality metrics. The objective is to determine the association of surgeon and hospital case volume on patient outcomes after an aortic root replacement for aortic root aneurysms. METHODS: From 2009 to 2014, 4629 Medicare patients underwent an aortic root replacement for a root aneurysm. Procedures were performed by 1276 surgeons at 718 hospitals. Patients with endocarditis, aortic rupture, or Type-A dissection were excluded. Procedural volume was defined as mean number of cases performed each year during the study period. The impact of hospital and surgeon volume on adjusted 30-day mortality was analyzed as a continuous variable using adjusted logistic regression with cubic splines. RESULTS: After an aortic root replacement, we observed a nonlinear reduction in the adjusted odds ratio for 30-day mortality as surgeon and hospital volume increased. Surgeons that performed approximately five cases/year and hospitals that completed approximately five cases/year had the greatest reduction in the odds of perioperative death. Patients treated at high-volume hospitals (≥4.5 cases/year) had a lower risk for 30-day postoperative stroke (hazard ratio [HR] = 0.51, p = .008), myocardial infarction (HR = 0.49, p = .016), hemodialysis (HR = 0.44, p = .005), and reoperation (HR = 0.48, p = .003). Additionally, patients treated with high-volume surgeons (≥9 cases/year) had lower risk for stroke (HR = 0.65, p = .005), hemodialysis (HR = 0.65, p = .03), sepsis (HR = 0.62, p = .03), and reoperation (HR = 0.67, p = .004). CONCLUSION: Among Medicare patients undergoing an aortic root replacement, there is a strong inverse relationship between annualized surgeon and hospital case volume and postoperative outcomes. Procedural volume is an important quality metric for this high-risk procedure.

Bivalirudin dosing during prolonged intermittent renal replacement therapy: a case report.

As patients transition between dialysis modalities, and from the intra- to the inter-dialytic period, medications with a narrow therapeutic index that are cleared in dialysis may require dose adjustments and close monitoring. Three cases of patients receiving bivalirudin while converting from continuous to prolonged intermittent renal replacement therapy are reported. Details provided include flow rates and ultrafiltrate volume. In these cases, it appears pre-emptive dose adjustments may be unwarranted, and clinicians should be aware of potential rebound after cessation of dialysis.

Cancer cachexia in a mouse model of oxidative stress.

BACKGROUND: Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer-related deaths. Oxidative stress is a critical player in the induction and progression of age-related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia. METHODS: Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline (saline) into the hind flank of female wild-type mice or Sod1KO mice at approximately 4 months of age. The tumour developed for 3 weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild-type and Sod1KO saline and tumour-bearing mice. Data were analysed by two-way ANOVA with Tukey-Kramer post hoc test when significant F ratios were determined and α was set at 0.05. Unless otherwise noted, results in abstract are mean ±SEM. RESULTS: Muscle mass and cross-sectional area were significantly reduced, in tumour-bearing mice. Metabolic enzymes were dysregulated in Sod1KO mice and cancer exacerbated this phenotype. NMJ fragmentation was exacerbated in tumour-bearing Sod1KO mice. Myofibrillar protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.00847 ± 0.00205; wildtype LLC, 0.0211 ± 0.00184) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0180 ± 0.00118; Sod1KO LLC, 0.0490 ± 0.00132). Muscle mitochondrial oxygen consumption was reduced in tumour-bearing mice compared with saline-injected wild-type mice. Mitochondrial protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.0204 ± 0.00159; wild-type LLC, 0.167 ± 0.00157) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0231 ± 0.00108; Sod1 KO LLC, 0.0645 ± 0.000631). Sciatic nerve conduction velocity was decreased in tumour-bearing wild-type mice (wild-type saline, 38.2 ± 0.861; wild-type LLC, 28.8 ± 0.772). Three out of eleven of the tumour-bearing Sod1KO mice did not survive the 3-week period following tumour implantation. CONCLUSIONS: Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.

Development of Persistent Opioid Use After Cardiac Surgery.

Importance: The overuse of opioids for acute pain management has led to an epidemic of persistent opioid use. Objective: To determine the proportion of opioid-naive patients who develop persistent opioid use after cardiac surgery and investigate the association between the initial amount of opioids prescribed at discharge and the likelihood of developing new persistent opioid use. Design, Setting, and Participants: This retrospective cohort study used data from a national administrative claims database from January 1, 2004, to December 31, 2016 and included 35 817 patients who underwent coronary artery bypass grafting (CABG) (25 673 [71.7%]) and heart valve (10 144 [28.3%]) procedures. All patients were opioid-naive within 180 days before the index procedure and filled an opioid prescription within 14 days after surgery. Exposures: Opioid medications after cardiac surgery. Main Outcomes and Measures: The proportion of opioid-naive patients who developed new persistent opioid use within 90 to 180 days after surgery was determined. Oral morphine equivalents (OMEs) were calculated for the first opioid prescription filled after discharge. A multivariable logistic regression with cubic splines was used to analyze the association among the OMEs at discharge and likelihood of developing persistent opioid use. Results: Of the 25 673 patients who underwent CABG, the mean (SD) age for those without (n = 23 064) vs with (n = 2609) persistent opioid use was 62.9 (9.8) years vs 61.6 (9.7) years, respectively, and the number who were men were 18 758 (81.3%) vs 1998 (76.6%). Of the 10 144 patients who underwent heart valve surgery, the mean (SD) age for those without (n = 9343) vs with (n = 821) persistent opioid use was 63.2 (12.4) years vs 61.2 (12.5) years, respectively, and the number who were men were 6378 (68.3%) vs 511 (62.2%). Persistent opioid use is a substantial concern after cardiac surgery and occurred in 2609 patients undergoing CABG (10.2%) and 821 valve surgery patients (8.1%; P = .001). The likelihood for developing persistent opioid use was decreased among heart valve surgery recipients (odds ratio [OR], 0.78; P < .001) and increased for patients who were women; younger; with preoperative congestive heart failure, chronic lung disease, diabetes, kidney failure, chronic pain, and alcoholism; and those taking preoperative benzodiazepines and muscle relaxants (women: OR, 1.15 [95% CI, 1.03-1.26]; younger age: OR, 1.02 [95% CI, 1.01-1.02]; congestive heart failure: OR, 1.17 [95% CI, 1.06-1.30]; chronic lung disease: OR, 1.32 [95% CI, 1.19-1.45]; diabetes: OR, 1.27 [95% CI, 1.15-1.40]; kidney failure: OR, 1.17 [95% CI, 1.00-1.37]; chronic pain: OR, 2.71 [95% CI, 2.10-3.56]; alcoholism: OR, 1.56 [95% CI, 1.23-2.00]; benzodiazepines: OR, 1.71 [95% CI, 1.52-1.91]; muscle relaxants: OR, 1.74 [95% CI, 1.51-2.02]; all P < .001). Furthermore, we found that when patients were prescribed more than approximately 300 mg of OMEs at discharge, they had a significantly increased risk of new persistent opioid use than with lower opioid prescriptions. Conclusions and Relevance: Opioids are used extensively after cardiothoracic surgery and nearly 1 of 10 patients will continue to use opioids over 90 days after surgery. Furthermore, higher OMEs prescribed at discharge were significantly associated with developing persistent use. Centers must adopt protocols to increase patient education and limit opioid prescriptions after discharge.