Single-stranded DNA aptamers are oligonucleotides of ≈50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies ...may address limitations of existing proteomic techniques, including low sample throughput, which have hindered proteomic analyses of large cohorts.
To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures 1129 proteins to a clinically relevant perturbational model of planned myocardial infarction (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood samples were obtained before and at 10 and 60 minutes after PMI, and protein changes were assessed by repeated-measures analysis of variance. The generalizability of our PMI findings was evaluated in a spontaneous myocardial infarction cohort (Wilcoxon rank-sum). We then tested the platform's ability to detect associations between proteins and Framingham Risk Score components in the Framingham Heart Study, performing regression analyses for each protein versus each clinical trait.
We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15; P<5.70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15; P<2.30E-4); >85% were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf-related protein 4, a WNT pathway inhibitor (peak increase 124%, P=1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P=1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with spontaneous myocardial infarction (n=46; P<0.05). Framingham Heart Study analyses revealed 156 significant protein associations with the Framingham Risk Score (n=899), including aminoacylase 1 (β=0.3386, P=2.54E-22) and trigger factor 2 (β=0.2846, P=5.71E-17). Furthermore, we developed a novel workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate aptamer specificity.
Our results highlight an emerging proteomics tool capable of profiling >1000 low-abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies and large human cohorts, as well.
Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the ...reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.
MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of all mediators of atherosclerosis, and some reports have suggested increased levels in coronary artery disease (CAD) ...and acute myocardial infarction (AMI). However, the potential of miRNAs as biomarkers or predictors of disease remains to be established.
We designed a study comprising 150 patients (50 Control, 50 Stable CAD, and 50 ST Elevation Myocardial Infarction (STEMI)), and measured plasma miRNAs in each. We then determined the ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) risk factors, to discriminate between CAD vs Control, and STEMI vs Control.
Three miRNAs (miR15a-5p, miR16-5p, and miR93-5p) were significantly increased in Stable CAD vs Control groups and one (miR146a-5p) was significantly decreased in Stable CAD vs Control. One miRNA – miR499a-5p – was significantly increased in the STEMI group compared to Controls. After adjustment for FHS risk factors, miR93-5p levels remained an independent predictor of the presence of CAD (Odds Ratio OR=8.76, P=0.002). All 4 miRNAs improved discriminatory power for CAD over FHS alone in ROC analysis. Similarly, after adjustment for risk factors miR499-5p remained an independent predictor of STEMI (OR=3.03, P=0.001) and improved discriminatory power for STEMI in ROC analyses.
We identified 4 miRNAs that were differentially expressed among stable CAD and control patients, and 1 miRNA that was elevated in STEMI patients vs controls. MiR93-5p was the strongest predictor of CAD after adjustment for traditional risk factors, suggesting potential diagnostic utility.
Background Nearly 30% of patients with newly formed ileostomies require hospital readmission from severe dehydration or associated complications. This contributes to significant morbidity and rising ...healthcare costs associated with this procedure. Our aim was to design and pilot a novel program to decrease readmissions in this patient population. Study Design An agreement was established with Visiting Nurse Health System (VNHS) in March 2015 that incorporated regular home visits with clinical triggers to institute surgeon-supervised corrective measures aimed at preventing patient decompensation associated with hospital readmissions. Thirty-day readmission data for patients managed with and without VNHS support for 10.5 months before and after implementation of this new program were collected. Results Of 833 patients with small bowel procedures, 162 were ileostomies with 47 in the VNHS and 115 in the non-VNHS group. Before program implementation, VNHS (n = 24) and non-VNHS patients (n = 54) had similar readmission rates (20.8% vs 16.7%). After implementation, VNHS patients (n = 23) had a 58% reduction in hospital readmission (8.7%) and non-VNHS patient hospital readmissions (n = 61) increased slightly (24.5%). Total cost of readmissions per patient in the cohort decreased by >80% in the pilot VNHS group. Conclusions Implementation of a novel program reduced the 30-day readmission rate by 58% and cost of readmissions per patient by >80% in a high risk for readmission patient population with newly created ileostomies. Future efforts will expand this program to a greater number of patients, both institutionally and systemically, to reduce the readmission-rate and healthcare costs for this high-risk patient population.
Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of ...monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.
Unsolicited patient observations are associated with risk of medical malpractice claims. Because lawsuits may be triggered by an unexpected adverse outcome superimposed on a strained ...patient-physician relationship, a question remains as to whether behaviors that generate patient dissatisfaction might also contribute to the genesis of adverse outcomes themselves.
To examine whether patients of surgeons with a history of higher numbers of unsolicited patient observations are at greater risk for postoperative complications than patients whose surgeons generate fewer such unsolicited patient observations.
This retrospective cohort study used data from 7 academic medical centers participating in the National Surgical Quality Improvement Program and the Vanderbilt Patient Advocacy Reporting System from January 1, 2011, to December 31, 2013. Patients older than 18 years included in the National Surgical Quality Improvement Program who underwent inpatient or outpatient operations at 1 of the participating sites during the study period were included. Patients were excluded if the attending surgeon had less than 24 months of data in the Vanderbilt Patient Advocacy Reporting System preceding the date of the operation. Data analysis was conducted from June 1, 2015, to October 20, 2016.
Unsolicited patient observations for the patient's surgeon in the 24 months preceding the date of the operation.
Postoperative surgical or medical complications as defined by the National Surgical Quality Improvement Program within 30 days of the operation of interest.
Among the 32 125 patients in the cohort (13 230 men, 18 895 women; mean SD age, 55.8 15.8 years), 3501 (10.9%) experienced a complication, including 1754 (5.5%) surgical and 2422 (7.5%) medical complications. Prior unsolicited patient observations for a surgeon were significantly associated with the risk of a patient having any complication (odds ratio, 1.0063; 95% CI, 1.0004-1.0123; P = .03), any surgical complication (odds ratio, 1.0104; 95% CI, 1.0022-1.0186; P = .01), any medical complication (odds ratio, 1.0079; 95% CI, 1.0009-1.0148; P = .03), and being readmitted (odds ratio, 1.0088, 95% CI, 1.0024-1.0151; P = .007). The adjusted rate of complications was 13.9% higher for patients whose surgeon was in the highest quartile of unsolicited patient observations compared with patients whose surgeon was in the lowest quartile.
Patients whose surgeons have large numbers of unsolicited patient observations in the 24 months prior to the patient's operation are at increased risk of surgical and medical complications. Efforts to promote patient safety and address risk of malpractice claims should continue to focus on surgeons' ability to communicate respectfully and effectively with patients and other medical professionals.
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•The feasibility of NAD+ repletion in human myocardial tissue using the NAD precursor NR is demonstrated in our study.•In a preclinical model, it is demonstrated that both ...prophylactic and therapeutic NAD+ repletion is equally effective in addressing HFpEF.•Despite favorable effects on cardiac metabolism, the HFpEF phenotype is not rescued by dietary intervention and weight loss. In contrast, the findings in our preclinical study suggest that NAD+ repletion emerges as a promising strategy for phenotype rescue.
Heart failure (HF) with left ventricular diastolic dysfunction is a growing global concern. This study evaluated myocardial oxidized nicotinamide adenine dinucleotide (NAD+) levels in human systolic and diastolic HF and in a murine model of HF with preserved ejection fraction, exploring NAD+ repletion as therapy. We quantified myocardial NAD+ and nicotinamide phosphoribosyltransferase levels, assessing restoration with nicotinamide riboside (NR). Findings show significant NAD+ and nicotinamide phosphoribosyltransferase depletion in human diastolic HF myocardium, but NR successfully restored NAD+ levels. In murine HF with preserved ejection fraction, NR as preventive and therapeutic intervention improved metabolic and antioxidant profiles. This study underscores NAD+ repletion’s potential in diastolic HF management.
To determine the relationship between complications after 3 common general surgery procedures and per-episode hospital finances.
With impending changes in health care reimbursement, maximizing the ...value of care delivered is paramount. Data on the relative clinical and financial impact of postoperative complications are necessary for directing surgical quality improvement efforts.
We reviewed the medical records of patients enrolled in the American College of Surgeons' National Surgical Quality Improvement Program who underwent pancreaticoduodenectomy, hepatectomy, and colectomy at a single academic institution between September 2009 and August 2012. Clinical outcomes data were subsequently linked with hospital billing data to determine hospital finances associated with each episode. We describe the association between postoperative complications, hospital length of stay, and different financial metrics. Multivariable linear regression modeling tested linear association between postoperative outcomes and cost data.
There was a positive association between the number of surgical complications, payments, length of stay, total charges, total costs, and contribution margin for the three procedures. Multivariable models indicated that complications were independently associated with total cost among the selected procedures. Payments increased with complications, offsetting increased costs.
In the current fee-for-service environment, the financial incentives are misaligned with quality improvement efforts. As we move to a value-driven method of reimbursement, administrators and health care providers alike will need to focus on improving the quality of patient care while remaining conscious of the cost of care delivered. Reducing complications effectively improves value.
Postoperative acute renal failure is a major cause of morbidity and mortality in colon and rectal surgery. Our objective was to identify preoperative risk factors that predispose patients to ...postoperative renal failure and renal insufficiency, and subsequently develop a risk calculator. Using the National Surgical Quality Improvement Program Participant Use Files database, all patients who underwent colorectal surgery in 2009 were selected (n = 21,720). We identified renal complications during the 30-day period after surgery. Using multivariate logistic regression analysis, a predictive model was developed. The overall incidence of renal complications among colorectal surgery patients was 1.6 per cent. Significant predictors include male gender (adjusted odds ratio OR: 1.8), dependent functional status (OR: 1.5), preoperative dyspnea (OR: 1.5), hypertension (OR: 1.6), preoperative acute renal failure (OR: 2.0), American Society of Anesthesiologists class ≥3 (OR: 2.2), preoperative creatinine >1.2 mg/dL (OR: 2.8), albumin <3.5 g/dL (OR: 1.8), and emergency operation (OR: 1.5). This final model has an area under the curve (AUC) of 0.79 and was validated with similar excellent discrimination (area under the curve: 0.76). Using this model, a risk calculator was developed with excellent predictive ability for postoperative renal complications in colorectal patients and can be used to aid clinical decision-making, patient counseling, and further research on measures to improve patient care.
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