Search

Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids played a central role in precipitating the opioid crisis. Despite an estimated heritability of 25–50%, the genetic architecture of chronic pain is not well characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 125 independent genetic loci, 82 of which are novel. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level, and cognitive traits. Integration of the GWAS findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, beta-blockers, and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.

Collective movement and organization of cell monolayers are important for wound healing and tissue development. Recent experiments highlighted the importance of liquid crystal order within these layers, suggesting that +1 topological defects have a role in organizing tissue morphogenesis. We study fibroblast organization, motion and proliferation on a substrate with micron-sized ridges that induce +1 and −1 topological defects using simulation and experiment. We model cells as selfpropelled deformable ellipses that interact via a Gay-Berne potential. Unlike earlier work on other cell types, we see that density variation near defects is not explained by collective migration. We propose instead that fibroblasts have different division rates depending on their area and aspect ratio. This model captures key features of our previous experiments: the alignment quality worsens at high cell density and, at the center of the +1 defects, cells can adopt either highly anisotropic or primarily isotropic morphologies. Experiments performed with different ridge heights confirm a new prediction of this model: suppressing migration across ridges promoteshighercell density at the +1 defect. Our work enables new mechanisms for tissue patterning using topological defects.

Background: Single photon emission computed tomography (SPECT) has limited ability to identify multivessel and microvascular coronary artery disease. Gamma cameras with cadmium zinc telluride detectors allow the quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR). However, evidence of its accuracy is limited, and of its reproducibility is lacking. We aimed to validate 99m Tc-sestamibi SPECT MBF and MFR using standard and spline-fitted reconstruction algorithms compared with 13 N-ammonia positron emission tomography in a cohort of patients with known or suspected coronary artery disease and to evaluate the reproducibility of this technique. Methods: Accuracy was assessed in 34 participants who underwent dynamic 99m Tc-sestamibi SPECT and 13 N-ammonia positron emission tomography and reproducibility in 14 participants who underwent 2 99m Tc-sestamibi SPECT studies, all within 2 weeks. A rest/pharmacological stress single-day SPECT protocol was performed. SPECT images were reconstructed using a standard ordered subset expectation maximization (OSEM) algorithm with (N=21) and without (N=30) application of spline fitting. SPECT MBF was quantified using a net retention kinetic model‚ and MFR was derived as the stress/rest MBF ratio. Results: SPECT global MBF with splines showed good correlation with 13 N-ammonia positron emission tomography (r=0.81, P P P P =0.07, for MBF and MFR, respectively). Reproducibility of global MBF estimates with splines in paired SPECT scans was good (r=0.77, P P P =0.3). There were no significant differences in MBF or MFR between the 2 reproducibility scans independently of the reconstruction algorithm ( P >0.05 for all). Conclusions: MBF and MFR quantification using 99m Tc-sestamibi cadmium zinc telluride SPECT with spatiotemporal spline fitting improved the correlation with 13 N-ammonia positron emission tomography flow estimates and test/retest reproducibility. The use of splines may represent an important step toward the standardization of SPECT flow estimation.

Despite a global decrease in suicide rates in recent years, death by suicide has increased in the United States. It is therefore imperative to identify the risk factors associated with suicide attempts in order to combat this growing epidemic. In this study, we use an explainable-artificial intelligence method, iterative Random Forest, to predict suicide attempts using data from the Million Veteran Program. Our predictive model incorporates multiple environmental variables (e.g., elevation, light wavelength absorbance, temperature, humidity, etc) at ZIP code-level geospatial resolution. We additionally consider demographic variables from the American Community Survey as well as the number of firearms and alcohol vendors per 10,000 people in order to assess the contributions of proximal environment, access to means, and restraint decrease to suicide attempts. Our results show that geographic areas with higher concentrations of married males living with spouses are predictive of lower rates of suicide attempts, whereas geographic areas where males are more likely to live alone and to rent housing are predictive of higher rates of suicide attempts. We also identified climatic features that were associated with suicide attempt risk by age group. Additionally, we observed that firearms and alcohol vendors were associated with increased risk for suicide attempts irrespective of the age group examined, but that their effects were small in comparison to the top features. Taken together, our findings highlight the importance of social determinants and environmental factors in understanding suicide risk among veterans.

Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. Here we dramatically relax GWAS stringency by orders of magnitude and apply GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks from diverse lines of evidence. From multiple GWAS summary statistics of suicide attempt, a complex psychiatric phenotype, GRIN identified additional genes that replicated across independent cohorts and retained genes that were more biologically interrelated despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways to influence suicidal behavior and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate that GRIN is a useful community resource for improving the signal to noise ratio of GWAS results.

The primary aims of this study were to determine the correlation between absolute quantitative 99mTc-pyrophosphate metrics and traditional measures of cardiac amyloid burden and to measure the intraobserver repeatability of the quantitative metrics. Methods: We studied 72 patients who underwent 99mTc-pyrophosphate SPECT/CT using a novel general-purpose cadmium-zinc-telluride-based SPECT/CT system. The clinical standard for these studies is visual grading (with grades of 0, 1, 2, and 3 indicating myocardial uptake absent, less than rib uptake, equal to rib uptake, or more than rib uptake, respectively). A visual grade of 2 or more was considered positive. For 72 patients, SUVmax, SUVmean, cardiac amyloid activity (CAA; i.e., SUVmean × left ventricular [LV] volume), and percentage injected dose (%ID) were calculated, and visual grading was performed. The correlation was determined between the 4 quantitative metrics or visual grades and the LV mass index (LVMI) (indexed to body surface area on echocardiography, 67 patients). For a subset of 11 patients, the correlation was determined between the visual or quantitative metrics and the extracellular volume (ECV) on cardiac MRI. Normal linear regression was used to compare the standardized association of each of the 4 quantitative metrics with LVMI, as a surrogate for amyloid burden. Receiver-operating-characteristic curve analysis was used to determine the diagnostic accuracy of quantitative metrics, using visual grading as the reference standard. The intraobserver repeatability of generating quantitative metrics was also determined. Results: All 4 quantitative metrics were highly accurate, with an area under the receiver-operating-characteristic curve of more than 0.96 for diagnosis of transthyretin cardiac amyloidosis. SUVmax, SUVmean, CAA, %ID, and visual grade were moderately positively correlated with LVMI (r = 0.485 for %ID) and strongly positively correlated, albeit in a small cohort, with ECV (r = 0.873, SUVmax). Intraobserver repeatability was excellent, with less than a 2% coefficient of variation for SUVmax, %ID, and CAA and 3.8% for SUVmean All 4 quantitative metrics had a standardized effect of more than 0.324 on LVMI; the largest standardized effect was 0.485, for %ID. Conclusion: In this first (to our knowledge) study of 99mTc-pyrophosphate cardiac imaging using a novel cadmium-zinc-telluride SPECT/CT scanner, SUVmax, SUVmean, CAA, and %ID measured by absolute quantitation of 99mTc-pyrophosphate were moderately correlated with LVMI and strongly correlated, albeit in a small cohort, with ECV. The intraobserver repeatability of generating the quantitative metrics was excellent.

The primary aims of this study were to determine the correlation between absolute quantitative (99m)Tc-pyrophosphate metrics and traditional measures of cardiac amyloid burden and to measure the intraobserver repeatability of the quantitative metrics. Methods: We studied 72 patients who underwent (99m)Tc-pyrophosphate SPECT/CT using a novel general-purpose cadmium-zinc-telluride–based SPECT/CT system. The clinical standard for these studies is visual grading (with grades of 0, 1, 2, and 3 indicating myocardial uptake absent, less than rib uptake, equal to rib uptake, or more than rib uptake, respectively). A visual grade of 2 or more was considered positive. For 72 patients, SUV(max), SUV(mean), cardiac amyloid activity (CAA; i.e., SUV(mean) × left ventricular [LV] volume), and percentage injected dose (%ID) were calculated, and visual grading was performed. The correlation was determined between the 4 quantitative metrics or visual grades and the LV mass index (LVMI) (indexed to body surface area on echocardiography, 67 patients). For a subset of 11 patients, the correlation was determined between the visual or quantitative metrics and the extracellular volume (ECV) on cardiac MRI. Normal linear regression was used to compare the standardized association of each of the 4 quantitative metrics with LVMI, as a surrogate for amyloid burden. Receiver-operating-characteristic curve analysis was used to determine the diagnostic accuracy of quantitative metrics, using visual grading as the reference standard. The intraobserver repeatability of generating quantitative metrics was also determined. Results: All 4 quantitative metrics were highly accurate, with an area under the receiver-operating-characteristic curve of more than 0.96 for diagnosis of transthyretin cardiac amyloidosis. SUV(max), SUV(mean), CAA, %ID, and visual grade were moderately positively correlated with LVMI (r = 0.485 for %ID) and strongly positively correlated, albeit in a small cohort, with ECV (r = 0.873, SUV(max)). Intraobserver repeatability was excellent, with less than a 2% coefficient of variation for SUV(max), %ID, and CAA and 3.8% for SUV(mean). All 4 quantitative metrics had a standardized effect of more than 0.324 on LVMI; the largest standardized effect was 0.485, for %ID. Conclusion: In this first (to our knowledge) study of (99m)Tc-pyrophosphate cardiac imaging using a novel cadmium-zinc-telluride SPECT/CT scanner, SUV(max), SUV(mean), CAA, and %ID measured by absolute quantitation of (99m)Tc-pyrophosphate were moderately correlated with LVMI and strongly correlated, albeit in a small cohort, with ECV. The intraobserver repeatability of generating the quantitative metrics was excellent.

Monotonic and cyclic tests were carried out to determine strength and stiffness characteristics of 2.44 m (8 ft) long shear connections with 8 mm and 10 mm diameter self-tapping screws. The goal of this research is to compare test values of cross-laminated timber (CLT) diaphragm connections in seismic force-resisting systems to the design values calculated from formulas in the National Design Specification for Wood Construction (USA) and the Eurocode. Understanding and quantifying the behavior of these shear connections will provide structural engineers with increased confidence in designing these components, especially with regard to the seismic force-resisting systems. Ratios of the experimental yield strength (from the yield point on the load-deflection curve) to factored design strength were in the range of 2.1–6.1. In the ASCE 41-13 acceptance criteria analysis, the m-factors for the Life Safety performance level in cyclic tests ranged from 1.6 to 1.8 for surface spline connections and from 0.9 to 1.7 for cyclic half-lap connections. The half-lap connections with a unique combination of angled and vertical screws performed exceptionally well with both high, linear elastic initial stiffness and ductile, post-peak behavior.

It has been well established that many types of rapidly dividing normal and diseased cells require an increased amount of folate for DNA replication and repair as well as cellular metabolism. Thus one of folate's cognate receptors, Folate Receptor 1 (FOLR1) is usually up-regulated in rapidly dividing cells, including many types of cancerous tumors. Because zebrafish have become a model organism for understanding conserved vertebrate cellular pathways and human disease, there has been an increased need to identify and elucidate orthologous zebrafish genes that are central to known human maladies. The cells of all early animal embryos go through a phase of rapid division (cleavage) where particular cell cycle checkpoints are skipped until a specification event occurs directing these embryonic stem cells to their fated germ layer cell type. Interestingly, this rapid cell division that ignores cell cycle checkpoints is also observed in many cancers. Developing blastula and tumor cells both require folr1 expression to obtain folate. In this report we have identified the expression pattern of the zebrafish gene zgc:165502, located on chromosome 15. Using computational and comparative methods and molecular biology techniques such as reverse transcription polymerase chain reaction (RT-PCR) and whole mount in situ hybridization (WISH) during embryogenesis, we demonstrate that zgc:165502 is the zebrafish orthologue of the human FOLR1 gene. Understanding when and where FOLR1 orthologues are expressed in different biomedical model organisms such as the zebrafish will help researchers design better experiments to study the endogenous FOLR1 activity.

not Available.