Instrumented Static and Reactive Balance in Collegiate Athletes: Normative Values and Minimal Detectable Change.

CONTEXT: Wearable sensors are increasingly popular in concussion research because of their objective quantification of subtle balance deficits. However, normative data and minimum detectable change values are necessary to serve as a references for diagnostic use and tracking longitudinal recovery. OBJECTIVE: Identify normative values and minimal detectable change values for instrumented static and reactive balance tests, an instrumented static Mediolateral Root Mean Square (ML RMS) sway standing balance assessment, and the instrumented, modified Push & Release (I-mP&R), respectively. DESIGN: Cross-Sectional Study. SETTING: Clinical Setting. PATIENTS OR OTHER PARTICIPANTS: Normative static ML RMS sway and I-mP&R data were collected on 377 (n=184 females) healthy National Collegiate Athletic Association Division I athletes at the beginning of their competitive seasons. Test-retest data were collected in 36 healthy control athletes based on standard recovery timelines after concussion. RESULTS: Descriptive statistics, intraclass correlation coefficients (ICC), and minimal detectable change (MDC) values were calculated for primary outcomes of mediolateral (ML) root-mean-square (RMS) sway in a static double limb-stance standing on firm ground and a foam block, and time to stability and latency from the I-mP&R in single- and dual-task conditions. RESULTS: Normative outcomes across static ML RMS sway and I-mP&R were sensitive to sex and type of footwear. ML RMS sway demonstrated moderate reliability in the firm condition (ICC=0.73; MDC=2.7cm/s2), but poor reliability in the foam condition (ICC=0.43; MDC=11.1cm/s2). Single- and dual-task time to stability from the I-mP&R exhibited good reliability (ICC=0.84 and 0.80, respectfully; MDC=0.25s, 0.59s, respectfully). Latency from the I-mP&R had poor to moderate reliability (ICC=0.38, 0.55; MDC=107ms, 105ms). CONCLUSIONS: Sex-matched references should be used for instrumented static and reactive balance assessments. Footwear may explain variability in static ML RMS sway and time to stability of the I-mP&R. Moderate-to-good reliability suggest time to stability from the I-mP&R and ML RMS static sway on firm ground can be used for longitudinal assessments.

How Caregivers Support Children's Emotion Regulation: Construct Validation of the Parental Assistance With Child Emotion Regulation (PACER) Questionnaire.

Caregivers play a crucial role in supporting the development of their children's emotion regulation. This study validated the Parental Assistance with Child Emotion Regulation (PACER) Questionnaire in a sample of 491 caregivers (M = 32.89 years) of young children ≤ 5 years. Exploratory structural equation modeling provided evidence of the instrument's ability to assess parental support for 10 distinct emotion regulation strategies that match the intended design of the instrument. Latent profile analysis revealed three distinct caregiver profiles characterized by above-average support for strategies that previously have been shown to be predictive of adaptive outcomes, maladaptive outcomes, or mixed-outcomes, respectively. Results add to existing literature that suggests the PACER is a valid and reliable assessment of caregiver-implemented support of emotion regulation strategies for children ≤ 5 years old. Evidence of distinct caregiver profiles highlights opportunities for prevention and intervention efforts to bolster extrinsic support for adaptive emotion regulation strategies. This instrument may be well-suited to capturing changes throughout the early developmental period, in addition to monitoring caregiver-facing interventions promoting optimal emotion regulation in children.

The Potential of Topoisomerase Inhibitor-Based Antibody-Drug Conjugates.

DNA topoisomerases are essential enzymes that stabilize DNA supercoiling and resolve entanglements. Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. To increase accumulation of TOP1 inhibitors in cancer cells through the targeting of tumors, TOP1 inhibitor antibody-drug conjugates (TOP1-ADC) have been developed and marketed. Some TOP1-ADCs have shown enhanced therapeutic efficacy compared to prototypical anti-cancer ADCs, such as T-DM1. Here, we review various types of camptothecin-based TOP1 inhibitors and recent developments in TOP1-ADCs. We then propose key points for the design and construction of TOP1-ADCs. Finally, we discuss promising combinatorial strategies, including newly developed approaches to maximizing the therapeutic potential of TOP1-ADCs.

Sensitivity and Specificity of MRI in Diagnosing Concomitant Meniscal Injuries With Pediatric and Adolescent Acute ACL Tears.

Background: Preoperative diagnosis of concomitant meniscal tears in pediatric and adolescent patients with acute anterior cruciate ligament (ACL) deficiency is challenging. Purpose: To investigate the diagnostic performance of magnetic resonance imaging (MRI) in detecting meniscal injuries for pediatric and adolescent patients with acute ACL tears. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: The authors retrospectively identified patients aged ≤18 years who underwent acute ACL reconstruction between 2006 and 2018 at 2 tertiary academic hospitals. The primary outcomes were arthroscopically confirmed medial, lateral, or any (defined as medial and/or lateral) meniscal tears. To control for chronically deficient knees, patients must have received their MRI study within 4 weeks of injury and must have undergone surgery no more than 8 weeks after their MRI study. Preoperative MRI reports were compared with the gold standard of arthroscopically confirmed tears to calculate sensitivity, specificity, positive predictive value, and negative predictive value. In a secondary analysis, patients were stratified by age into 2 groups (≤13 or ≥14 years), body mass index-for-age data from the Centers for Disease Control were used to classify patients as obese or nonobese, and differences between sensitivity and specificity proportions were analyzed using chi-square test for homogeneity. Results: Overall, 406 patients with a mean age of 15.4 years (range, 10-18 years) were identified. The sensitivity, specificity, positive predictive value, and negative predictive value were as follows: for lateral meniscal (LM) tears, 51.0%, 86.5%, 78.3%, and 65.0%; for medial meniscal tears, 83.2%, 80.6%, 62.3%, and 92.5%; and for any meniscal tear, 75.0%, 72.1%, 81.5%, and 63.8%, respectively. In the stratified analysis, MRI was less specific for the following diagnoses: any meniscal tear in patients aged ≤13 years (P = .048) and LM tears in obese patients (P = .020). Conclusion: The diagnostic ability of MRI to predict meniscal injuries present at acute ACL reconstruction was moderate. Performance was poorest at the lateral meniscus, where MRI failed to detect 97 tears that were found arthroscopically. Specificity was significantly lower in younger patients for any meniscal tear and in obese patients for LM tears.

Patellofemoral joint cartilage restoration with particulated juvenile allograft in patients under 21 years old.

BACKGROUND: Patellofemoral joint cartilage defects are difficult to treat due to their unique thickness and topography. PURPOSE: To report the postoperative outcomes of patients age 21 and younger treated with particulated juvenile allograft cartilage (PJAC) for full-thickness cartilaginous defects of the patellofemoral joint. The primary aim was to report surgical outcomes and complication rates, as well as return to sport activity. A secondary aim was to provide objective scores of defect restoration by magnetic resonance imaging (MRI) assessment. METHODS: A retrospective review of all PJAC cases conducted between 2012 and 2019 at a single tertiary care urban musculoskeletal institution was conducted. Patients 21 years old or younger with minimum clinical follow up of 1 year and postoperative MRI at a minimum of 6 months were included. Cartilage restoration by MRI was independently assessed using the International Cartilage Repair Society's (ICRS) standardized system. RESULTS: Thirty four patients, 36 knees, were included, with mean age 16.1 ± 3.1 years old. Return to sport rate among patients who participated in a sport preoperatively was 100%. On independent MRI assessment, two thirds of defects achieved an overall grade of normal or nearly normal, while 28 patients (78%) had majority defect fill. Primary graft failure occurred in two cases and one patient experienced a surgical complication. CONCLUSION: Restoration of patellofemoral chondral defects in young patients with particulated juvenile allograft results in satisfactory short-term outcomes and postoperative MRI appearance, along with high rates of return to sport and low rate of complications and graft failure. What is known about the subject: Patellofemoral joint cartilage defects are difficult to treat due to their unique thickness and topography. Several cartilage restoration techniques are available, but these rarely achieve the same mechanical properties as native hyaline cartilage. PJAC is a cell-based technique that has demonstrated promise since its introduction in 2007. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE: This series of patients adds the largest single cohort of pediatric and adolescent patients who receive PJAC for defects of the patellofemoral joint. Surgeons treating patients in this age group should be aware of every technique, and their respective outcomes.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Near-electrode pH change for voltammetric detection of insoluble lead carbonate.

Lead contamination of drinking water is a concern to all inhabitants of old cities where lead pipes and soldering are still present. Simple on-site electrochemical detection methods are promising technologies that have gained attention recently. However, conventional electrochemical techniques only quantify soluble forms of lead in water without accounting for insoluble particulates. Herein, a simple voltammetric technique for quantification of insoluble lead species is reported. Lead carbonate (PbCO3) was used as a model compound to show the possibility of detecting particulate lead species directly in solution without chemical treatment. Specifically, electrochemical generation of protons was used as an alternative method to dissolve PbCO3 and thus obtain a more realistic assessment of lead contamination. Lead was detected using cathodic stripping square wave voltammetry (CSSWV). After applying a high oxidizing potential to the electrode immersed in a PbCO3 solution with solid PbCO3 particulates, a significant increase in current was observed as compared to that of a saturated PbCO3 solution. The signal was proportional to the amount of added PbCO3, even when the solubility limit was exceeded. Thus, the combination of a local pH change with CSSWV provides a simple, rapid, and reagentless method for an in-situ detection of insoluble lead species.

Fontan-associated liver disease and total cavopulmonary anatomical flow effectors.

OBJECTIVE: We investigated a relationship between a composite index comprised of Fontan-circuit anatomical features and hepatic fibrosis scores from biopsy. METHODS: We identified living extracardiac Fontan patients, ≥7 years old and ≥5 but <20 years postoperative, that underwent cardiac catheterization and transvenous liver biopsy between March 2012 and September 2020. We divided patients into anatomical groups and applied a risk score to each patient. We compared average anatomical risk scores with average hepatic total fibrosis scores by group. RESULTS: We identified 111 patients that met inclusion criteria. After excluding four patients, we assigned 107 to one of 12 anatomical variant groups (n ≥ 3). For the 107, the average age at liver biopsy was 14 ± 6 years old. Of the 107, 105 (98%) were New York Heart Association Class 1. We found average anatomical risk scores by group correlated with average total fibrosis scores by group (R = 0.8; p = .005). An average Fontan duration to biopsy of 10 ± 1 years was similar for all 12 anatomical groups. We found no other clinical variables, laboratory, or hemodynamic values that trended with anatomical risk scores or hepatic total fibrosis scores. CONCLUSIONS: In a cohort of relatively young, stable extracardiac Fontan patients, average composite anatomical risk scores strongly correlated with average hepatic total fibrosis scores by anatomical group. These findings suggest that some anatomical variants in extracardiac Fontan patients are associated with higher Fontan-associated liver disease (FALD)-related hepatic total fibrosis scores than others, despite similar Fontan durations.

Fontan-Associated Anatomical Variants and Hepatic Fibrosis.

OBJECTIVE: We hypothesized that a relationship between post-Fontan hepatic fibrosis and anatomical variants might exist. METHODS: Attempting to limit confounding variables, we analyzed data from living, stable, post-extracardiac Fontan patients who underwent cardiac catheterization and transvenous hepatic biopsy procedures between March 2012 and June 2020. RESULTS: We identified 120 patients who met the inclusion criteria. Of the 120, 35 (29%) had pulmonary artery stents. For the 35 with pulmonary artery stents, the average total fibrosis score was 3.2 ± 1.9 and the fibrosis progression rate was 0.36 ± 0.33, and for those with no pulmonary artery stents, the total fibrosis score was 2.6 ± 1.8 and the fibrosis progression rate was 0.27 ± 0.33 (P = .13 and P = .11, respectively). Of the 120, 65 had functional univentricles of right ventricular type. Of these 65, 27 had pulmonary artery stents. For the 27 with pulmonary artery stents, the average total fibrosis score was 3.4 ± 1.8 and the average fibrosis progression rate was 0.39 ± 0.30, and for the 38 without pulmonary artery stents, the average fibrosis score was 2.3 ± 1.5 and the average fibrosis progression rate was 0.23 ± 0.21 (P = .01 for comparison of both values). CONCLUSIONS: This study's findings suggest that a post-extracardiac Fontan with a functional univentricle of right ventricular type plus a pulmonary artery stent may have more advanced liver pathology than those without a pulmonary artery stent at similar Fontan duration years and ages at liver biopsy.

Early Operative Versus Delayed Operative Versus Nonoperative Treatment of Pediatric and Adolescent Anterior Cruciate Ligament Injuries: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment options for pediatric and adolescent anterior cruciate ligament (ACL) injuries include early operative, delayed operative, and nonoperative management. Currently, there is a lack of consensus regarding the optimal treatment for these injuries. PURPOSE/HYPOTHESIS: The purpose was to determine the optimal treatment strategy for ACL injuries in pediatric and adolescent patients. We hypothesized that (1) early ACL reconstruction results in fewer meniscal tears than delayed reconstruction but yields no difference in knee stability and (2) when compared with nonoperative management, any operative management results in fewer meniscal tears and cartilage injuries, greater knee stability, and higher return-to-sport rates. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: A systematic search of databases was performed including PubMed, Embase, and Cochrane Library using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Inclusion criteria were a pediatric and adolescent patient population (≤19 years old at surgery), the reporting of clinical outcomes after treatment of primary ACL injury, and original scientific research article. Exclusion criteria were revision ACL reconstruction, tibial spine avulsion fracture, case report or small case series (<5 patients), non-English language manuscripts, multiligamentous injuries, and nonclinical studies. RESULTS: A total of 30 studies containing 50 cohorts and representing 1176 patients met our criteria. With respect to nonoperative treatment, knee instability was observed in 20% to 100%, and return to preinjury level of sports ranged from 6% to 50% at final follow-up. Regarding operative treatment, meta-analysis results favored early ACL reconstruction over delayed reconstruction (>12 weeks) for the presence of any meniscal tear (odds ratio, 0.23; P = .006) and irreparable meniscal tear (odds ratio, 0.31; P = .001). Comparison of any side-to-side differences in KT-1000 arthrometer testing did not favor early or delayed ACL reconstruction in either continuous mean differences (P = .413) or proportion with difference ≥3 mm (P = .181). Return to preinjury level of competition rates for early and delayed ACL reconstruction ranged from 57% to 100%. CONCLUSION: Delaying ACL reconstruction in pediatric or adolescent patients for >12 weeks significantly increased the risk of meniscal injuries and irreparable meniscal tears; however, early and delayed operative treatment achieved satisfactory knee stability. Nonoperative management resulted in high rates of residual knee instability, increased risk of meniscal tears, and comparatively low rates of return to sports.

Cranial synchondroses of primates at birth.

Cranial synchondroses are cartilaginous joints between basicranial bones or between basicranial bones and septal cartilage, and have been implicated as having a potential active role in determining craniofacial form. However, few studies have examined them histologically. Using histological and immunohistochemical methods, we examined all basicranial joints in serial sagittal sections of newborn heads from nine genera of primates (five anthropoids, four strepsirrhines). Each synchondrosis was examined for characteristics of active growth centers, including a zonal distribution of proliferating and hypertrophic chondrocytes, as well as corresponding changes in matrix characteristics (i.e., density and organization of Type II collagen). Results reveal three midline and three bilateral synchondroses possess attributes of active growth centers in all species (sphenooccipital, intrasphenoidal, presphenoseptal). One midline synchondrosis (ethmoseptal) and one bilateral synchondrosis (alibasisphenoidal synchondrosis [ABS]) are active growth centers in some but not all newborn primates. ABS is oriented more anteriorly in monkeys compared to lemurs and bushbabies. The sphenoethmoidal synchondrosis (SES) varies at birth: in monkeys, it is a suture-like joint (i.e., fibrous tissue between the two bones); however, in strepsirrhines, the jugum sphenoidale is ossified while the mesethmoid remains cartilaginous. No species possesses an SES that has the organization of a growth plate. Overall, our findings demonstrate that only four midline synchondroses have the potential to actively affect basicranial angularity and facial orientation during the perinatal timeframe, while the SES of anthropoids essentially transitions toward a "suture-like" function, permitting passive growth postnatally. Loss of cartilaginous continuity at SES and reorientation of ABS distinguish monkeys from strepsirrhines.

Fontan venovenous collaterals and hepatic fibrosis.

OBJECTIVE: We hypothesized that a relationship might exist between angiographically demonstrable, post-Fontan venovenous collaterals, and hepatic fibrosis. METHODS: We analyzed data from post-Fontan patients that underwent cardiac catheterization and transvenous-hepatic biopsy procedures between March 2012 and March 2020. From innominate vein angiography, we determined those that either had or lacked venovenous collaterals. Additionally, we examined data from post-Fontan patients that underwent hepatic ultrasound, shear-wave elastography between January 2017 and March 2020. RESULTS: We identified 164 patients that met inclusion criteria. Of the 164, 101 (62%) had venovenous collaterals. Of the 101 with collaterals, average total fibrosis score (TFS) was 3.2 and the average rate of fibrosis progression was 0.28 vs an average TFS of 2.1 and an average fibrosis progression rate of 0.22 for those without collaterals (P = .00001 and P = .01, respectively). Of the 101 with collaterals, oxygen saturation was 91% ± 4% vs 93% ± 3% (P = .048) without collaterals. Of the 164, 86 (52%) underwent ultrasound shear-wave elastography. Of the 86 patients undergoing elastography, 50 (58%) were performed in those with collaterals, and 36 (42%) in those without collaterals. For the 50 with collaterals, average elastography values were 13.3 vs 11.2 kPa for the 36 without collaterals (P = .006). We found no statistically significant differences for age at biopsy, Fontan duration, Fontan-type, type of functional univentricle, laboratory, clinical, or hemodynamic values between those with or without collaterals. CONCLUSIONS: The presence of angiographically demonstrated venovenous collaterals was associated with statistically, significantly more advanced liver fibrosis than those without collaterals.

The Rate of Hepatic Fibrosis Progression in Patients Post-Fontan.

This investigation analyzed the rate of hepatic fibrosis progression in post-Fontan patients that underwent hepatic biopsy. The study cohort comprised post-Fontan patients that underwent cardiac catheterization and transvenous liver biopsy between March 2012 and September 2019. We identified 126 patients that met inclusion criteria. Of the 126, 27 (21%) had a lateral tunnel Fontan, and 99 (79%) had an extracardiac Fontan. For the 27 lateral tunnel Fontan patients, age at Fontan was 4 ± 2 years, and for the 99 extracardiac Fontan patients age at Fontan was 4 ± 2 years (p = 0.98). For the 27 lateral tunnel Fontan patients, the average total fibrosis score was 3.0 ± 1.5; and for the 99 extracardiac Fontan patients, the average total fibrosis was 2.7 ± 1.7 (p = 0.48). For the lateral tunnel Fontan patients, the average Fontan duration was 20 ± 6 years; and for the 99 extracardiac Fontan patients, the average Fontan duration was 11 ± 5 years (p < 0.001). For the 27 lateral tunnel Fontan patients, the average rate of fibrosis progression was 0.16 ± 0.10 total fibrosis score/year; and for the 99 extracardiac Fontan patients, the average rate of fibrosis progression was 0.30 ± 0.23 total fibrosis score/year (p < 0.001). In conclusion, our findings suggest that those with extracardiac Fontans have a faster rate of hepatic fibrosis progression than those with lateral tunnel Fontans. More extensive or multi-institutional studies will be needed to confirm these findings and define the clinical significance of discrepant rates of hepatic fibrosis in post-Fontan patients.

Consumer Prices for Surgical Management of Ankle Arthritis: Limited Availability and Wide Variability.

BACKGROUND: Healthcare costs for the surgical management of ankle arthritis continue to rise. Patients are generally unaware of the prices of the services they use. Understanding the costs associated with surgical management of ankle arthritis is an important facet of patient care. The purposes of this study were to (1) determine the access to the surgical cost of total ankle arthroplasty (TAAs) and ankle arthrodesis and (2) the variability of the price between the two procedures. METHODS: Fifty foot and ankle centers (25 academic, 25 private) that perform TAAs and ankle arthrodeses were contacted using a standardized patient script. The described patient was a 63-year-old man who had failed conservative treatment of ankle arthritis. Each institution was contacted up to three times in an attempt to obtain a full-bundled surgical quote for a TAA and an ankle arthrodesis. RESULTS: Twenty-one centers (42%, 14 academic, 7 private) were able to provide a quote for a TAA and an ankle arthrodesis. The mean bundled price for a TAA was $50,332 (SD ± $25,744), with the mean academic and private center quote being $56,529 and $37,937, respectively. The mean bundled price for an ankle arthrodesis was $41,756 (SD ± $26,033), with the mean academic and private center quote being $48,116 and $29,037, respectively. No statistically significant difference was found between the bundled prices for TAA and ankle arthrodesis. DISCUSSION: This study demonstrated limited availability of consumer prices for TAA and ankle arthrodesis. When comparing different institutions for surgical management of ankle arthritis, there was a wide range of quotes for both TAA and ankle arthrodesis. When comparing the choice of surgical management for ankle arthritis, no statistically significant difference was observed in price between TAA and ankle arthrodesis.

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

A composite noninvasive index correlates with liver fibrosis scores in post-Fontan patients: Preliminary findings.

OBJECTIVE: We hypothesized that clinic-based, hepatic-ultrasound, elastography measurements, either alone or in combination with other noninvasive variables, might correlate with liver-biopsy fibrosis scores in patients post-Fontan. METHODS: Between March 2012 and February 2017, we identified patients post-Fontan that underwent elective cardiac catheterization and simultaneous transvenous hepatic biopsy. From this group, we selected patients that met inclusion criteria for liver-ultrasound, shear-wave elastography. Utilizing the results of elastography, laboratory testing, and time post-Fontan, we constructed a composite Fontan hepatic index as a sum of elastography measurements in kilopascals, model for end-stage liver disease excluding INR scores, and the square root of the number of years post-Fontan. Further, we analyzed correlations between Fontan hepatic index values and fibrosis scores from hepatic biopsy. RESULTS: We identified a total of 79 post-Fontan patients that underwent cardiac catheterization and liver biopsy. Of the 79 patients, 53 met inclusion criteria, and 32 consented to undergo hepatic-ultrasound elastography. Of the 32 that underwent elastography, data from 30 patients was used for analysis. We found no statistically significant differences in demographics, laboratory values, or cardiac catheterization data between the 30 included patients and the 21 that did not participate. Utilizing data from the 30 included patients, we found a strong, highly statistically significant correlation between the Fontan hepatic index values and total fibrosis scores (R = 0.8, P < .00001). However, the cohort size prevented reliable discriminating cut-off values for the range of total fibrosis scores. CONCLUSIONS: In a small cohort of patients post-Fontan, preliminary findings suggest that the composite Fontan hepatic index might be a clinically useful, noninvasive method of serially monitoring for hepatic fibrosis. Further studies, with large patient cohorts, are necessary to validate our findings and develop clinically useful discriminatory cutoff values.