Designing graduate training programs in conservation medicine-producing the right professionals with the right tools.

New challenges to human, animal, and ecosystem health demand novel solutions: New diseases are emerging from new configurations of humans, their domestic animals and wildlife; new pressures on once robust and resilient ecosystems are compromising their integrity; synthetic compounds and engineered organisms, new to the natural world, are spreading unpredictably around the globe. Globalization provides opportunities for infectious organisms to gain access to new hosts, changing in distribution and virulence. What type of training should be developed to provide professionals with the right tools to meet these challenges? In this article, we offer recommendations for developing academic programs in conservation medicine. We discuss the need for, and the advantages to, using a conservation medicine approach to address real world situations and present illustrations of how this is applied today. We suggest a core set of skills that are needed in a conservation medicine practitioner, and recommend key considerations for designing new conservation medicine training programs. We review existing programs that offer conservation medicine content, and provide examples of where opportunities exist for those interested in pursuing a conservation medicine career

Professional Partnerships and Matching in Obstetrics

Theory indicates that internally-differentiated professional partnerships can promote matching between heterogeneous consumers and professionals, particularly when consumers have imperfect information or markets have barriers to referrals between firms. We test this in obstetrics markets, relying on random assignment of patients to physicians to generate unbiased measures of a physician's treatment style and skill, and on simulations to measure a physician's specialization. Consumers match to professionals along all three dimensions -- specialization, style and skill -- based on consumers' observed characteristics and unobserved preferences. We conclude that internally-differentiated partnerships promote matching in ways that improve consumers' welfare and health.

PlexinD1 and Semaphorin Signaling Are Required in Endothelial Cells for Cardiovascular Development

AbstractThe identification of new signaling pathways critical for cardiac morphogenesis will contribute to our understanding of congenital heart disease (CHD), which remains a leading cause of mortality in newborn children worldwide. Signals mediated by semaphorin ligands and plexin receptors contribute to the intricate patterning of axons in the central nervous system. Here, we describe a related signaling pathway involving secreted class 3 semaphorins, neuropilins, and a plexin receptor, PlexinD1, expressed by endothelial cells. Interruption of this pathway in mice results in CHD and vascular patterning defects. The type of CHD caused by inactivation of PlexinD1 has previously been attributed to abnormalities of neural crest. Here, we show that this form of CHD can be caused by cell-autonomous endothelial defects. Thus, molecular programs that mediate axon guidance in the central nervous system also function in endothelial cells to orchestrate critical aspects of cardiac morphogenesis

Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies.

BACKGROUND: Prostate cancer (PCa) diagnosis is challenging because efforts for effective, timely treatment of men with significant cancer typically result in over-diagnosis and repeat biopsies. The presence or absence of epigenetic aberrations, more specifically DNA-methylation of GSTP1, RASSF1, and APC in histopathologically negative prostate core biopsies has resulted in an increased negative predictive value (NPV) of ∼90% and thus could lead to a reduction of unnecessary repeat biopsies. Here, it is investigated whether, in methylation-positive men, DNA-methylation intensities could help to identify those men harboring high-grade (Gleason score ≥7) PCa, resulting in an improved positive predictive value. METHODS: Two cohorts, consisting of men with histopathologically negative index biopsies, followed by a positive or negative repeat biopsy, were combined. EpiScore, a methylation intensity algorithm was developed in methylation-positive men, using area under the curve of the receiver operating characteristic as metric for performance. Next, a risk score was developed combining EpiScore with traditional clinical risk factors to further improve the identification of high-grade (Gleason Score ≥7) cancer. RESULTS: Compared to other risk factors, detection of DNA-methylation in histopathologically negative biopsies was the most significant and important predictor of high-grade cancer, resulting in a NPV of 96%. In methylation-positive men, EpiScore was significantly higher for those with high-grade cancer detected upon repeat biopsy, compared to those with either no or low-grade cancer. The risk score resulted in further improvement of patient risk stratification and was a significantly better predictor compared to currently used metrics as PSA and the prostate cancer prevention trial (PCPT) risk calculator (RC). A decision curve analysis indicated strong clinical utility for the risk score as decision-making tool for repeat biopsy. CONCLUSIONS: Low DNA-methylation levels in PCa-negative biopsies led to a NPV of 96% for high-grade cancer. The risk score, comprising DNA-methylation intensity and traditional clinical risk factors, improved the identification of men with high-grade cancer, with a maximum avoidance of unnecessary repeat biopsies. This risk score resulted in better patient risk stratification and significantly outperformed current risk prediction models such as PCPTRC and PSA. The risk score could help to identify patients with histopathologically negative biopsies harboring high-grade PCa. Prostate 76:1078-1087, 2016. © 2016 The Authors. The Prostate Published by Wiley Periodicals, Inc.MDxHealthThis is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Wiley

Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart

AbstractDevelopmental abnormalities in endocardial cushions frequently contribute to congenital heart malformations including septal and valvular defects. While compelling evidence has been presented to demonstrate that members of the TGF-β superfamily are capable of inducing endothelial-to-mesenchymal transdifferentiation in the atrioventricular canal, and thus play a key role in formation of endocardial cushions, the detailed signaling mechanisms of this important developmental process, especially in vivo, are still poorly known. Several type I receptors (ALKs) for members of the TGF-β superfamily are expressed in the myocardium and endocardium of the developing heart, including the atrioventricular canal. However, analysis of their functional role during mammalian development has been significantly complicated by the fact that deletion of the type I receptors in mouse embryos often leads to early embryonal lethality. Here, we used the Cre/loxP system for endothelial-specific deletion of the type I receptor Alk2 in mouse embryos. The endothelial-specific Alk2 mutant mice display defects in atrioventricular septa and valves, which result from a failure of endocardial cells to appropriately transdifferentiate into the mesenchyme in the AV canal. Endocardial cells deficient in Alk2 demonstrate decreased expression of Msx1 and Snail, and reduced phosphorylation of BMP and TGF-β Smads. Moreover, we show that endocardial cells lacking Alk2 fail to delaminate from AV canal explants. Collectively, these results indicate that the BMP type I receptor ALK2 in endothelial cells plays a critical non-redundant role in early phases of endocardial cushion formation during cardiac morphogenesis

Validation of \u3cem\u3eIn Vivo\u3c/em\u3e 2D Displacements from Spiral Cine DENSE at 3T

BACKGROUND: Displacement Encoding with Stimulated Echoes (DENSE) encodes displacement into the phase of the magnetic resonance signal. Due to the stimulated echo, the signal is inherently low and fades through the cardiac cycle. To compensate, a spiral acquisition has been used at 1.5T. This spiral sequence has not been validated at 3T, where the increased signal would be valuable, but field inhomogeneities may result in measurement errors. We hypothesized that spiral cine DENSE is valid at 3T and tested this hypothesis by measuring displacement errors at both 1.5T and 3T in vivo. METHODS: Two-dimensional spiral cine DENSE and tagged imaging of the left ventricle were performed on ten healthy subjects at 3T and six healthy subjects at 1.5T. Intersection points were identified on tagged images near end-systole. Displacements from the DENSE images were used to project those points back to their origins. The deviation from a perfect grid was used as a measure of accuracy and quantified as root-mean-squared error. This measure was compared between 3T and 1.5T with the Wilcoxon rank sum test. Inter-observer variability of strains and torsion quantified by DENSE and agreement between DENSE and harmonic phase (HARP) were assessed by Bland-Altman analyses. The signal to noise ratio (SNR) at each cardiac phase was compared between 3T and 1.5T with the Wilcoxon rank sum test. RESULTS: The displacement accuracy of spiral cine DENSE was not different between 3T and 1.5T (1.2 ± 0.3 mm and 1.2 ± 0.4 mm, respectively). Both values were lower than the DENSE pixel spacing of 2.8 mm. There were no substantial differences in inter-observer variability of DENSE or agreement of DENSE and HARP between 3T and 1.5T. Relative to 1.5T, the SNR at 3T was greater by a factor of 1.4 ± 0.3. CONCLUSIONS: The spiral cine DENSE acquisition that has been used at 1.5T to measure cardiac displacements can be applied at 3T with equivalent accuracy. The inter-observer variability and agreement of DENSE-derived peak strains and torsion with HARP is also comparable at both field strengths. Future studies with spiral cine DENSE may take advantage of the additional SNR at 3T

Semaphorin-Plexin Signaling Guides Patterning of the Developing Vasculature

AbstractMajor vessels of the vertebrate circulatory system display evolutionarily conserved and reproducible anatomy, but the cues guiding this stereotypic patterning remain obscure. In the nervous system, axonal pathways are shaped by repulsive cues provided by ligands of the semaphorin family that are sensed by migrating neuronal growth cones through plexin receptors. We show that proper blood vessel pathfinding requires the endothelial receptor PlexinD1 and semaphorin signals, and we identify mutations in plexinD1 in the zebrafish vascular patterning mutant out of bounds. These results reveal the fundamental conservation of repulsive patterning mechanisms between axonal migration in the central nervous system and vascular endothelium during angiogenesis

High Resolution Cine Displacement Encoding with Stimulated Echoes (DENSE) at 3T with Navigator Feedback for Quantification of Cardiac Mechanics

Background: Measures of cardiac mechanics such as myocardial wall strain are better predictors of outcomes in patients with heart disease compared to traditional clinical measures and ejection fraction. Cine displacement encoding with stimulated echoes (DENSE) is an ideal method for quantifying cardiac motion which encodes tissue displacement in the phase of the MR signal and provides pixel-level resolution for quantifying cardiac mechanics. To date, DENSE has been implemented with resolution limited to 2-3 pixels across the myocardium. While this resolution is higher than most other techniques for quantifying cardiac mechanics, it may limit the ability of DENSE to quantify finer details such as transmural strains (subendocardial, midmyocardial and subepicardial) and right ventricular mechanics. We hypothesized that it is possible to efficiently increase the resolution of DENSE by a factor of 4 utilizing a navigator feedback system. Methods: 10 subjects (age 27 ± 3) with normal ECG and no history of cardiovascular disease were consented. A 3.0T Siemens Tim Trio with a 6-element chest and 24-element spine coil was configured with a navigator feedback system. The feedback system projected the navigator image of the diaphragm to the subject in real time to optimize breathold position. Standard resolution 2D cine DENSE was acquired with: 6 spiral interleaves, FOV = 340 mm, matrix = 96 × 96, thickness = 8 mm, TE/TR = 1.08/17, flip angle = 20, averages = 1, navigator acceptance window = ± 3 mm. High resolution 2D cine DENSE images were acquired by quadrupling the number of spirals to 24, increasing the matrix to 256 × 256, and increasing the averages to 3. Three short- and two long-axis images were acquired with each technique. Left ventricular strains and torsion were compared between the techniques using Bland-Altman. Results: The high resolution images took 11 times longer to acquire but the navigator feedback system provided good efficiency (69 ± 9%) for a total acquisition time of roughly 5 minutes per slice. The high resolution images had excellent quality with a noticeable improvement over standard resolution. There was a systematic but negligible difference between standard and high resolution data for circumferential and longitudinal strains. Radial strains showed the largest differences consistent with a systematic under-estimation of radial strain from standard resolution DENSE. Torsion was not significantly different between the two methods. Conclusions: High resolution cine DENSE MRI with navigator feedback is feasible at 3T and produces high quality images with 4 times the resolution of standard DENSE. Left ventricular circumferential strains, longitudinal strains, and torsion showed negligible differences between high and low resolution DENSE. Radial strains were significantly different, potentially due to better accuracy with high resolution DENSE due to the increased number of pixels within the thickness of the myocardial wall

Quantification of Right Ventricular Function from Short-Axis Displacement-Encoded Images

Background Right ventricular (RV) function is important in many disease states, but is difficult to quantify from routine MR imaging. Previous work has shown that long-axis deformation/strain is the most critical contributor to global RV function; however, short-axis datasets allow for better coverage of the RV. Thus it would be ideal to be able to quantify RV long-axis function using short-axis slice orientations. We hypothesized that a stack of three-dimensional (3D) displacement encoded (DENSE) images could reliably quantify longitudinal deformation of the RV to overcome the need for acquiring additional long-axis views of the RV. Methods A contiguous stack of cine short-axis DENSE images encompassing the entire RV was acquired with 3D encoding in eight healthy volunteers (Age: 27 ± 3 years) using a 3T Siemens Tim Trio scanner. Endo- and epicardial boundaries were manually drawn on each image to generate a 3D reconstruction of the RV myocardium. The measured displacement field was used to deform the mesh and longitudinal strains were computed at every point throughout the volume. For comparison to the short-axis stack with 3D encoding, a standard four-chamber DENSE image with two-dimensional in-plane displacement encoding was acquired. Similar to the 3D analysis, a mesh was deformed using the measured displacements and was subsequently used to determine longitudinal RV strain values. For comparison with the four-chamber data, only short-axis points lying within the four-chamber imaging slices were used to compute peak longitudinal strain. All strains were compared using a two-tailed paired t-test. Results Right ventricular longitudinal strains derived from short-axis 3D DENSE images (-20 ± 4%) were comparable to values obtained from four-chamber images (-16 ± 2%) (p = 0.14). In addition to obtaining information solely at the four-chamber/short-axis intersection, we computed a global RV longitudinal strain of -17 ± 2% from 3D DENSE data (p = 0.64 relative to four-chamber only). Bland Altman analysis yielded a non-significant bias of 3 ± 11% between four-chamber and short-axis longitudinal strain estimates. Conclusions We have demonstrated that short-axis 3D DENSE imaging allows for accurate characterization of right ventricular longitudinal strain compared to a standard long-axis four-chamber acquisition which is typically used to look at RV function. In addition, 3D DENSE acquired in a short-axis orientation allows for more complete coverage of the RV compared to acquisitions based on long-axis image planes. It is likely that the more complete assessment of RV function provided by 3D DENSE could potentially improve upon the accuracy, reproducibility and prognostic ability of common echocardiographic techniques such as the tricuspid annular plane systolic excursion (TAPSE), but future work will need to investigate this

Two-Dimensional Estimates of Left Ventricular Strains are Significantly Affected by Through-Plane Motion

Background Advanced measures of cardiac mechanics such as left ventricular (LV) strains can be used in conjunction with classical biomarkers to gauge cardiovascular health and improve prediction of patient outcomes. Several imaging techniques, including displacement-encoded magnetic resonance imaging (DENSE), are used to non-invasively assess cardiac mechanics. These data are predominantly acquired in two dimensions (2D) due to simplified post-processing and shorter acquisition times; however, this type of acquisition and subsequent analysis cannot account for through-plane motion caused by longitudinal contraction of the left ventricle. We hypothesized that through-plane motion has a significant effect on 2D strain estimates. Methods Cine DENSE data were acquired in eight healthy volunteers (Age: 27 ± 3 years) with a 3T Siemens Tim Trio scanner. Short-axis slices with 2.8 mm in-plane resolution and an 8 mm slice thickness were acquired to span the entire LV. Displacements were encoded in both through-plane and in-plane directions with an effective temporal resolution of 34 ms. Endocardial and epicardial boundaries were delineated on the magnitude image of all short axis DENSE images. Radial and circumferential strains were computed based upon the deformation of the myocardium relative to the end-diastolic frame. Through-plane displacements were ignored for 2D analysis. For three-dimensional (3D) analysis, a 3D representation of the myocardium derived from the same endocardial and epicardial boundaries was deformed using the measured displacement field. The resulting radial and circumferential strain values were compared directly between the 2D and 3D analyses using a two-tailed paired t-test. Results Two dimensional processing consistently overestimated radial strain and underestimated circumferential strain. Peak circumferential strain was significantly different at the basal and mid-ventricular segments (p = 0.001 and 0.009, respectively). Peak radial strain decreased from the base to the apex in both 2D and 3D analyses; however, 2D significantly overestimated radial strain at the mid-ventricular and apical slices compared to 3D (p = 0.002). Global peak radial and circumferential strains from 3D were 30 ± 5% and -20 ± 2%, respectively, compared to 36 ± 5% and -18 ± 2% for 2D (both p \u3c 0.001). Conclusions Two-dimensional imaging methods for assessing left ventricular mechanics consistently overestimate radial strain and underestimate circumferential strain when compared to three-dimensional imaging. This limitation of two-dimensional imaging is likely due to the through-plane motion of the heart, which is ignored in two-dimensional techniques but easily accounted for when using three-dimensional techniques. Future research needs to determine the clinical and prognostic significance of this difference. Funding This research was funded in part by an NIH Early Independence Award to BKF (DP5 OD012132); contributions made by local businesses and individuals through a partnership between Kentucky Children\u27s Hospital and Children\u27s Miracle network; and the University of Kentucky Cardiovascular Research Center, grant UL1RR033173 from the National Center for Research Resources (NCRR), funded by the Office of the Director, National Institutes of Health (NIH) and supported by the NIH Roadmap for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources