Coronary Artery Bypass Graft Failure in Women: Incidence and Clinical Implications.

BACKGROUND: Women have worse outcomes after coronary artery bypass surgery (CABG) than men. OBJECTIVES: This study aimed to determine the incidence of CABG graft failure in women, its association with cardiac events, and whether it contributes to sex-related differences in outcomes. METHODS: A pooled analysis of individual patient data from randomized clinical trials with systematic imaging follow-up was performed. Multivariable logistic regression models were used to assess the association of graft failure with myocardial infarction and repeat revascularization between CABG and imaging (primary outcome) and death after imaging (secondary outcome). Mediation analysis was performed to evaluate the effect of graft failure on the association between female sex and risk of death. RESULTS: Seven randomized clinical trials (N = 4,413, 777 women) were included. At a median imaging follow-up of 1.03 years, graft failure was significantly more frequent among women than men (37.3% vs 32.9% at the patient-level and 20.5% vs 15.8% at the graft level; P = 0.02 and P < 0.001, respectively). In women, graft failure was associated with an increased risk of myocardial infarction and repeat revascularization (OR: 3.94; 95% CI: 1.79-8.67) and death (OR: 3.18; 95% CI: 1.73-5.85). Female sex was independently associated with the risk of death (direct effect, HR: 1.84; 95% CI: 1.35-2.50) but the association was not mediated by graft failure (indirect effect, HR: 1.04; 95% CI: 0.86-1.26). CONCLUSIONS: Graft failure is more frequent in women and is associated with adverse cardiac events. The excess mortality risk associated with female sex among CABG patients is not mediated by graft failure.

Insights into the pathophysiology and response of persistent spinal pain syndrome type 2 to spinal cord stimulation: a human genome-wide association study.

BACKGROUND: Spinal cord stimulation (SCS) provides pain relief for some patients with persistent spinal pain syndrome type 2 (PSPS 2), but the precise mechanisms of action and prognostic factors for a favorable pain response remain obscure. This in vivo human genome-wide association study provides some pathophysiological clues. METHODS: We performed a high-density oligonucleotide microarray analysis of serum obtained from both PSPS 2 cases and pain-free controls who had undergone lower back spinal surgery at the study site. Using multivariate discriminant analysis, we tried to identify different expressions between mRNA transcripts from PSPS 2 patients relative to controls, SCS responders to non-responders, or SCS responders to themselves before starting SCS. Gene ontology enrichment analysis was used to identify the biological processes that best discriminate between the groups of clinical interest. RESULTS: Thirty PSPS 2 patients, of whom 23 responded to SCS, were evaluated together with 15 pain-free controls. We identified 11 significantly downregulated genes in serum of PSPS 2 patients compared with pain-free controls and two significantly downregulated genes once the SCS response became apparent. All were suggestive of enhanced inflammation, tissue repair mechanisms and proliferative responses among the former. We could not identify any gene differentiating patients who responded to SCS from those who did not respond. CONCLUSIONS: This study points out various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response, inflammation and restorative processes.

Substrate Trapping in Polyketide Synthase Thioesterase Domains: Structural Basis for Macrolactone Formation.

Emerging antibiotic resistance requires continual improvement in the arsenal of antimicrobial drugs, especially the critical macrolide antibiotics. Formation of the macrolactone scaffold of these polyketide natural products is catalyzed by a modular polyketide synthase (PKS) thioesterase (TE). The TE accepts a linear polyketide substrate from the termina PKS acyl carrier protein to generate an acyl-enzyme adduct that is resolved by attack of a substrate hydroxyl group to form the macrolactone. Our limited mechanistic understanding of TE selectivity for a substrate nucleophile and/or water has hampered development of TEs as biocatalysts that accommodate a variety of natural and non-natural substrates. To understand how TEs direct the substrate nucleophile for macrolactone formation, acyl-enzyme intermediates were trapped as stable amides by substituting the natural serine OH with an amino group. Incorporation of the unnatural amino acid, 1,3-diaminopropionic acid (DAP), was tested with five PKS TEs. DAP-modified TEs (TE DAP ) from the pikromycin and erythromycin pathways were purified and tested with six full-length polyketide intermediates from three pathways. The erythromycin TE had permissive substrate selectivity, whereas the pikromycin TE was selective for its native hexaketide and heptaketide substrates. In a crystal structure of a native substrate trapped in pikromycin TE DAP , the linear heptaketide was curled in the active site with the nucleophilic hydroxyl group positioned 4 Å from the amide-enzyme linkage. The curled heptaketide displayed remarkable shape complementarity with the TE acyl cavity. The strikingly different shapes of acyl cavities in TEs of known structure, including those reported here for juvenimicin, tylosin and fluvirucin biosynthesis, provide new insights to facilitate TE engineering and optimization.

What is associated with painful polyneuropathy? A cross-sectional analysis of symptoms and signs in patients with painful and painless polyneuropathy.

ABSTRACT: It is still unclear how and why some patients develop painful and others painless polyneuropathy. The aim of this study was to identify multiple factors associated with painful polyneuropathies (NeuP). A total of 1181 patients of the multicenter DOLORISK database with painful (probable or definite NeuP) or painless (unlikely NeuP) probable or confirmed neuropathy were investigated clinically, with questionnaires and quantitative sensory testing. Multivariate logistic regression including all variables (demographics, medical history, psychological symptoms, personality items, pain-related worrying, life-style factors, as well as results from clinical examination and quantitative sensory testing) and machine learning was used for the identification of predictors and final risk prediction of painful neuropathy. Multivariate logistic regression demonstrated that severity and idiopathic etiology of neuropathy, presence of chronic pain in family, Patient-Reported Outcomes Measurement Information System Fatigue and Depression T-Score, as well as Pain Catastrophizing Scale total score are the most important features associated with the presence of pain in neuropathy. Machine learning (random forest) identified the same variables. Multivariate logistic regression archived an accuracy above 78%, random forest of 76%; thus, almost 4 out of 5 subjects can be classified correctly. This multicenter analysis shows that pain-related worrying, emotional well-being, and clinical phenotype are factors associated with painful (vs painless) neuropathy. Results may help in the future to identify patients at risk of developing painful neuropathy and identify consequences of pain in longitudinal studies.

Serotonin receptor-mediated vasorelaxation occurs primarily through 5-HT4 activation in bovine lateral saphenous vein.

To better understand mechanisms of serotonin- (5-HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5-HT or selective 5-HT receptor agonists. Vessels were pre-contracted with 1 × 10-4 M phenylephrine and exposed to increasing concentrations of 5-HT or 5-HT receptor agonists that were selective for 5-HT1B, 5-HT2B, 5-HT4, and 5-HT7. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction. At 1 × 10-7 M 5-HT, a relaxation was observed with an 88.7% decrease (p < 0.01) from the phenylephrine maximum. At 1 × 10-4 M 5-HT, a contraction was observed with a 165% increase (p < 0.01) from the phenylephrine maximum. Increasing concentrations of agonists selective for 5-HT2B, 5-HT4, or 5-HT7 resulted in a 27%, 92%, or 44% (p < 0.01) decrease from the phenylephrine maximum, respectively. Of these 5-HT receptor agonists, the selective 5-HT4 receptor agonist resulted in the greatest potency (-log EC50) value (6.30) compared with 5-HT2B and 5-HT7 receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5-HT4 in 5-HT-mediated vasorelaxation, blood vessels were exposed to either DMSO (solvent control) or a selective 5-HT4 antagonist (1 × 10-5 M) for 5-min prior to the phenylephrine pre-contraction and 5-HT additions. Antagonism of the 5-HT4 receptor attenuated the vasorelaxation caused by 5-HT. Approximately 94% of the vasorelaxation occurring in response to 5-HT could be accounted for through 5-HT4, providing strong evidence that 5-HT-mediated vasorelaxation occurs through 5-HT4 activation in bovine peripheral vasculature.

Mapping of long interspersed element-1 (L1) insertions by TIPseq provides information about sub chromosomal genetic variation in human embryos.

PURPOSE: Retrotransposons play important roles during early development when they are transiently de-repressed during epigenetic reprogramming. Long interspersed element-1 (L1), the only autonomous retrotransposon in humans, comprises 17% of the human genome. We applied the Single Cell Transposon Insertion Profiling by Sequencing (scTIPseq) to characterize and map L1 insertions in human embryos. METHODS: Sixteen cryopreserved, genetically tested, human blastocysts, were accessed from consenting couples undergoing IVF at NYU Langone Fertility Center. Additionally, four trios (father, mother, and embryos) were also evaluated. scTIPseq was applied to map L1 insertions in all samples, using L1 locations reported in the 1000 Genomes as controls. RESULTS: Twenty-nine unknown and unique insertions were observed in the sixteen embryos. Most were intergenic; no insertions were located in exons or immediately upstream of genes. The location or number of unknown insertions did not differ between euploid and aneuploid embryos, suggesting they are not merely markers of aneuploidy. Rather, scTIPseq provides novel information about sub-chromosomal structural variation in human embryos. Trio analyses showed a parental origin of all L1 insertions in embryos. CONCLUSION: Several studies have measured L1 expression at different stages of development in mice, but this study for the first time reports unknown insertions in human embryos that were inherited from one parent, confirming no de novo L1 insertions occurred in parental germline or during embryogenesis. Since one-third of euploid embryo transfers fail, future studies would be useful for understanding whether these sub-chromosomal genetic variants or de novo L1 insertions affect embryo developmental potential.

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.

Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.

Head-to-head comparison of leading blood tests for Alzheimer's disease pathology.

INTRODUCTION: Blood tests have the potential to improve the accuracy of Alzheimer disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes. METHODS: Plasma samples from the Alzheimers Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. RESULTS: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. DISCUSSION: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes.

Hepatitis C-related knowledge and attitude among adults on probation in a large US city.

BACKGROUND: Hepatitis C virus (HCV) continues to cause significant morbidity and mortality within the US, and disproportionately impacts those involved with the criminal justice system. Despite this, knowledge and attitudes regarding HCV treatment among adults on probation have not been well studied. We conducted a cross-sectional survey of adults on probation accessing on-site HCV testing and linkage services at the adult probation department in Denver, Colorado. The survey assessed general knowledge of HCV and HCV treatment, as well as attitudes surrounding HCV treatment that might reflect medical mistrust. We used bivariate and multivariable logistic regression to identify factors associated with previous HCV testing, previous HCV treatment, and HCV antibody positivity at the time the survey was conducted. RESULTS: A total of 402 participants completed all or a portion of the survey. 69% of the participants were cis-gender men; 29% were white, 27% were Black, and 30% were Hispanic/Latinx. Fewer than half of participants correctly identified that HCV infection is commonly asymptomatic (46%), that there is currently no vaccine that prevents HCV (19%), and that reinfection after treatment is possible (47%). Very few participants felt that side-effects (9%) or cost of treatment (10%) were barriers to care. Many participants believed that racial disparities exist in the treatment of HCV (59%). The belief that people who use substances are treated inequitably by health care providers was also commonly reported (35% of participants). Self-reported injection drug use and higher HCV-related knowledge were positively associated with previous testing for HCV. Higher HCV-related knowledge was positively associated with HCV antibody positivity at the time of survey completion, though the magnitude of the association was small. CONCLUSION: Interventions are needed to increase knowledge of HCV, to improve access to HCV testing and treatment, and to reduce bias associated with HCV and substance use within the probation population.

Long-Term Outcomes Following the Ross Procedure in Neonates and Infants: A Multi-Institutional Analysis.

OBJECTIVES: For neonates and infants with aortic valve pathology, the Ross procedure has historically been associated with high rates of morbidity and mortality. Data regarding long-term durability are lacking. METHODS: The international, multi-institutional Ross Collaborative included six tertiary-care centers. Infants who received a Ross operation between 1996-2016 (allowing a minimum five years of follow-up) were retrospectively identified. Serial echocardiograms were examined to study evolution in neoaortic size and function. RESULTS: Primary diagnoses for the 133 patients (n=30 neonates) included isolated aortic stenosis (AS; 14%, n=19), Shone complex (14%, n=19), and AS+other (excluding Shone complex; n=95, 71%) including arch obstruction (n=55), left ventricular hypoplasia (n=9), and mitral disease (>moderate stenosis or regurgitation, n=31). At the time of Ross, median age was 96 (IQR 36-186) days and median weight was 4.4 (3.6-6.5) kg. In-hospital mortality occurred in 13/133 (10%) patients (4/30 [13%] neonates). Post-discharge mortality occurred in 10/120 (8%) patients at a median 298 days post-Ross. Post-Ross neoaortic dilatation occurred, peaking at 4-5 standard deviations above normal at 2-3 years before returning to near-baseline z-score at a median follow-up of 11.5 [6.4-17.4] years. Autograft/LVOT reintervention was required in 5/120 (4%) patients at a median 10.3 [4.1-12.8] years. Freedom from >moderate neoaortic regurgitation (AR) was 86% at 15 years. CONCLUSIONS: Neonates and infants experience excellent post-discharge survival and long-term freedom from autograft reintervention and AR following Ross. Neoaortic dilatation normalizes in this population in the long-term. Increased consideration should be given to Ross in neonates and infants with aortic valve disease.

Outcomes of Concomitant Cardiac Surgical Procedures Performed During Pediatric Lung Transplantation in the United States.

Data on concomitant cardiac surgery (CCS) performed during pediatric lung transplantation (LTx) is limited. Therefore, we conducted a multi-institutional analysis to identify the incidence and outcomes of CCS in pediatric (< 18 years) LTx recipients by merging data (2004-2023) from the United Network for Organ Sharing (UNOS) and Pediatric Health Information System (PHIS) databases. Of the total of 596 pediatric LTx recipients, 87 (15%) underwent CCS. The majority of these cardiac surgeries were atrial septal defect (ASD) closure (90%) followed by aortic arch/descending aortic repair (3%), atrial repair (3%), ventricular septal defect closure (2%), patent ductus arteriosus ligation (2%), and tricuspid valve repair (2%). The median age at LTx was 3 years (IQR: 0-12). Pulmonary hypertension (PHT) was the predominant indication for LTx (54%). Survival to discharge was 94% and 5-years survival was 64%. Our findings indicate CCS in children undergoing LTx has acceptable outcomes.

Classification of Force-Time Metrics Into Lower-Body Strength Domains.

ABSTRACT: Geneau, MC, Carey, DL, Gastin, PB, Robertson, S, and James, LP. Classification of force-time metrics into lower-body strength domains. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this study was to classify force-time metrics into distinct lower-body strength domains using a systematic data reduction analysis. A cross-sectional design was used, whereby competitive field sport athletes (F = 39, M = 96) completed a series of drop jumps, squat jumps, countermovement jumps (CMJs), loaded CMJs, and 2 isometric tasks on portable force platforms, resulting in a total of 285 force-time performance metrics. The metrics were split into 4 test "families" and each was entered into a sparse principal component analysis (sPCA) model. A single metric from each component of each family-specific sPCA were selected based on the loading, reliability, and simplicity of the metric and entered into a second sPCA that included metrics across all tests. The final sPCA revealed 7 principal components each containing 2 metrics and explained a total of 53% variance of the dataset. The final principal components were interpreted as 7 lower-body strength domains: (a) dynamic force, (b) dynamic timing, (c) early isometric, (d) maximal isometric, (e) countermovement velocity, (f) reactive output, and (g) reactive timing. The findings demonstrate that a total of 7 metrics from a drop jump, CMJ, and isometric test can be used to represent ∼50% of variance in lower-body strength performance of field sport athletes. These results can help guide and simplify the lower-body strength diagnosis process in field sport athletes.

Risk of Pancreatitis After Endoscopic Ultrasound-Guided Fine Needle Aspiration of Pancreatic Cystic Lesions: A Systematic Review and Meta-Analysis.

BACKGROUND: Endoscopic ultrasound-guided fine-needle-aspiration (EUS-FNA) is frequently used to risk-stratify pancreatic cystic lesions (PCLs). Rising PCL incidence and developments in tissue acquisition and specimen analysis necessitate updated appraisal of EUS-FNA safety, particularly the risk of post-procedure pancreatitis, the most common EUS-FNA-related adverse event. Our systematic review aims to accurately quantify the risk of EUS-FNA-related pancreatitis to best inform decisions regarding EUS-FNA's optimal role in PCL workup. METHODS: We performed systematic searches in four databases from inception to April 2024 for original English-language studies investigating EUS-FNA-related pancreatitis. We extracted data on demographics and EUS-FNA-related pancreatitis risk, severity, and risk factors. These were meta-analyzed through the DerSimonian Laird Method using a random-effects model. Meta-regression of pancreatitis risk was performed to delineate associations with clinical and procedural characteristics. RESULTS: Sixty-four studies comprised 8086 patients and reported 110 EUS-FNA-related pancreatitis events. Pooled risk of EUS-FNA-related pancreatitis was 1.4% [95% CI, -0.8-3.5%; I2 = 0.00], which was predominantly of mild severity (67%) and uniformly non-fatal. Pancreatitis risk lacked significant association with sample size, age, sex, cyst size, needle caliber or passes, although we noted trends towards higher risk in studies published after 2015, those using higher gauge needles (19G vs. 22G/25G), and those performing EUS-TTNB. CONCLUSIONS: We note with high certainty that pancreatitis following EUS-FNA of PCLs is infrequent and mild in severity with no mortality in the included cohort. EUS-TTNB may serve as a significant risk factor for EUS-FNA-related pancreatitis risk; however, further studies are needed to delineate other predisposing characteristics.

Investigating the cognitive and affective dynamics of social media addiction: Insights from peer contexts.

Informed by the interaction of person-affect-cognition-execution (I-PACE) theory, the present studies examined the association between peer rejection, peer popularity, and social media addiction (SMA) at both between-person and within-person levels. Two distinct processes, the fear-driven/compensation-seeking process and the reward-driven process were explored. In Study 1, using a cross-sectional sample of high school students (N = 318), both processes were supported via different cognitive mediators. Support for the fear-driven/compensation-seeking process was demonstrated by finding that avoidance expectancy was a significant cognitive mediator between peer-nominated rejection and SMA. In turn, the reward-driven process was supported by the significant mediation of reward expectancy between peer-nominated popularity and SMA. In Study 2, using ecological momentary assessment with college students (N = 54), we found the fear-driven/compensation-seeking process partially supported through both between-person and within-person mediations. Specifically, negative affect and social media craving were two affective mediators that linked peer rejection and addictive social media use behaviors. On the other hand, the reward-driven process was predominantly supported by within-person mediations, in which positive affect and social media craving were found to be mediators of the relationship between peer popularity and addictive social media use behaviors. The results underscore that adolescents experiencing rejection tend to use social media to avoid negative feelings and compensate for interpersonal deficits, while adolescents experiencing popularity tend to use social media to maintain positive feelings and gain social rewards. Implications for the assessment, case formulation, and treatment of SMA in counseling practice are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Sharing Data from the Human Tumor Atlas Network through Standards, Infrastructure, and Community Engagement.

The Data Coordinating Center (DCC) of the Human Tumor Atlas Network (HTAN) has played a crucial role in enabling the broad sharing and effective utilization of HTAN data within the scientific community. Data from the first phase of HTAN are now available publicly. We describe the diverse datasets and modalities shared, multiple access routes to HTAN assay data and metadata, data standards, technical infrastructure and governance approaches, as well as our approach to sustained community engagement. HTAN data can be accessed via the HTAN Portal, explored in visualization tools-including CellxGene, Minerva, and cBioPortal-and analyzed in the cloud through the NCI Cancer Research Data Commons nodes. We have developed a streamlined infrastructure to ingest and disseminate data by leveraging the Synapse platform. Taken together, the HTAN DCC's approach demonstrates a successful model for coordinating, standardizing, and disseminating complex cancer research data via multiple resources in the cancer data ecosystem, offering valuable insights for similar consortia, and researchers looking to leverage HTAN data.

Effect of Data-Processing Methods on Acceleration Summary Metrics of GNSS Devices in Elite Australian Football.

This study aimed to measure the differences in commonly used summary acceleration metrics during elite Australian football games under three different data processing protocols (raw, custom-processed, manufacturer-processed). Estimates of distance, speed and acceleration were collected with a 10-Hz GNSS tracking technology device from fourteen matches of 38 elite Australian football players from one team. Raw and manufacturer-processed data were exported from respective proprietary software and two common summary acceleration metrics (number of efforts and distance within medium/high-intensity zone) were calculated for the three processing methods. To estimate the effect of the three different data processing methods on the summary metrics, linear mixed models were used. The main findings demonstrated that there were substantial differences between the three processing methods; the manufacturer-processed acceleration data had the lowest reported distance (up to 184 times lower) and efforts (up to 89 times lower), followed by the custom-processed distance (up to 3.3 times lower) and efforts (up to 4.3 times lower), where raw data had the highest reported distance and efforts. The results indicated that different processing methods changed the metric output and in turn alters the quantification of the demands of a sport (volume, intensity and frequency of the metrics). Coaches, practitioners and researchers need to understand that various processing methods alter the summary metrics of acceleration data. By being informed about how these metrics are affected by processing methods, they can better interpret the data available and effectively tailor their training programs to match the demands of competition.

Circulating Tumor DNA Predicts Early Recurrence Following Locoregional Therapy for Oligometastatic Colorectal Cancer.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan-Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar's test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

Engineered Heart Tissues for Standard 96-Well Tissue Culture Plates.

Engineered heart tissues (EHTs) have been shown to be a valuable platform for disease investigation and therapeutic testing by increasing human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) maturity and better recreating the native cardiac environment. The protocol detailed in this chapter describes the generation of miniaturized EHTs (mEHTs) incorporating hiPSC-CMs and human stromal cells in a fibrin hydrogel. This platform utilizes an array of silicone posts designed to fit in a standard 96-well tissue culture plate. Stromal cells and hiPSC-CMs are cast in a fibrin matrix suspended between two silicone posts, forming an mEHT that produces synchronous muscle contractions. The platform presented here has the potential to be used for high throughput characterization and screening of disease phenotypes and novel therapeutics through measurements of the myocardial function, including contractile force and calcium handling, and its compatibility with immunostaining.

Selection for early reproduction leads to accelerated aging and extensive metabolic remodeling in Drosophila melanogaster populations.

Experimental evolution studies that feature selection on life-history characters are a proven approach for studying the evolution of aging and variation in rates of senescence. Recently, the incorporation of genomic and transcriptomic approaches into this framework has led to the identification of hundreds of genes associated with different aging patterns. However, our understanding of the specific molecular mechanisms underlying these aging patterns remains limited. Here, we incorporated extensive metabolomic profiling into this framework to generate mechanistic insights into aging patterns in Drosophila melanogaster . Specifically, we characterized metabolomic change over time associated with accelerated aging in populations of D. melanogaster under selection for early reproduction compared to their controls. Using this data we: i) evaluated the evolutionary repeatability across the metabolome; ii) evaluated the value of the metabolome as a predictor of "biological age" in this system; and iii) identified specific metabolic pathways associated with accelerated aging. Generally, our findings suggest that the metabolome is a reliable predictor of age and senescence in populations that share a recent evolutionary history. Metabolomic analysis revealed that generations of selection for early reproduction resulted in highly repeatable alterations to the metabolome. Specifically, changes in carbohydrate, amino acid, and TCA cycle-related metabolite abundances over time point to metabolic remodeling that favors rapid early reproduction with long-term consequences for carbohydrate and protein utilization.

Reduced Auditory Perception and Brain Response with Quiet TMS Coil.

BACKGROUND: Electromagnetic forces in transcranial magnetic stimulation (TMS) coils generate a loud clicking sound that produces confounding auditory activation and is potentially hazardous to hearing. To reduce this noise while maintaining stimulation efficiency similar to conventional TMS coils, we previously developed a quiet TMS double containment coil (qTMS-DCC). OBJECTIVE: To compare the stimulation strength, perceived loudness, and EEG response between qTMS-DCC and a commercial TMS coil. METHODS: Nine healthy volunteers participated in a within-subject study design. The resting motor thresholds (RMTs) for qTMS-DCC and MagVenture Cool-B65 were measured. Psychoacoustic titration matched the Cool-B65 loudness to qTMS-DCC pulsed at 80, 100, and 120% RMT. Event-related potentials (ERPs) were recorded for both coils. The psychoacoustic titration and ERPs were acquired with the coils both on and 6 cm off the scalp, the latter isolating the effects of airborne auditory stimulation from body sound and electromagnetic stimulation. The ERP comparisons focused on a centro-frontal region that encompassed peak responses in the global signal. RESULTS: RMT did not differ significantly between the coils, with or without the EEG cap on the head. qTMS-DCC was perceived to be substantially quieter than Cool-B65. For example, qTMS-DCC at 100% coil-specific RMT sounded like Cool-B65 at 34% RMT. The general ERP waveform and topography were similar between the two coils, as were early-latency components, indicating comparable electromagnetic brain stimulation in the on-scalp condition. qTMS-DCC had a significantly smaller P180 component in both on-scalp and off-scalp conditions, supporting reduced auditory activation. CONCLUSIONS: The stimulation efficiency of qTMS-DCC matched Cool-B65, while having substantially lower perceived loudness and auditory-evoked potentials. Highlights: qTMS coil is subjectively and objectively quieter than conventional Cool-B65 coilqTMS coil at 100% motor threshold was as loud as Cool-B65 at 34% motor thresholdAttenuated coil noise reduced auditory N100 and P180 evoked response componentsqTMS coil enables reduction of auditory activation without masking.