Noninvasive imaging of vascular permeability to predict the risk of rupture in abdominal aortic aneurysms using an albumin-binding probe.

Abdominal aortic aneurysm (AAA) remains a fatal disease. Its development encompasses a complex interplay between hemodynamic stimuli on and changes in the arterial wall. Currently available biomarkers fail to predict the risk of AAA rupture independent of aneurysm size. Therefore, novel biomarkers for AAA characterization are needed. In this study, we used a mouse model of AAA to investigate the potential of magnetic resonance imaging (MRI) with an albumin-binding probe to assess changes in vascular permeability at different stages of aneurysm growth. Two imaging studies were performed: a longitudinal study with follow-up and death as endpoint to predict rupture risk and a week-by-week study to characterize AAA development. AAAs, which eventually ruptured, demonstrated a significantly higher in vivo MR signal enhancement from the albumin-binding probe (p = 0.047) and a smaller nonenhancing thrombus area compared to intact AAAs (p = 0.001). The ratio of albumin-binding-probe enhancement of the aneurysm wall to size of nonenhancing-thrombus-area predicted AAA rupture with high sensitivity/specificity (100%/86%). More advanced aneurysms with higher vascular permeability demonstrated an increased uptake of the albumin-binding-probe. These results indicate that MRI with an albumin-binding probe may enable noninvasive assessment of vascular permeability in murine AAAs and prediction of rupture risk.

Quantitative 3D Assessment of 68Ga-DOTATOC PET/MRI with Diffusion-Weighted Imaging to Assess Imaging Markers for Gastroenteropancreatic Neuroendocrine Tumors: Preliminary Results.

68Ga-DOTATOC PET/MRI combines the advantages of PET in the acquisition of metabolic-functional information with the high soft-tissue contrast of MRI. SUVs in tumors have been suggested to be a measure of somatostatin receptor expression. A challenge with receptor ligands is that the distribution volume is confined to tissues with tracer uptake, potentially limiting SUV quantification. In this study, various functional 3-dimensional SUV apparent diffusion coefficient (ADC) parameters and arterial tumor enhancement were tested for ability to characterize gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Methods: For this single-center, cross-sectional study, 22 patients with 24 histologically confirmed GEP NET lesions (15 men and 7 women; median age, 61 y; range, 43-81 y) who underwent hybrid 68Ga-DOTA PET/MRI at 3 T between January 2017 and July 2019 met the eligibility criteria. SUV, tumor-to-background ratio, total functional tumor volume, and mean and minimum ADC were measured on the basis of volumes of interest and examined with receiver-operating-characteristic analysis to determine cutoffs for differentiation between low- and intermediate-grade GEP NETs. The Spearman rank correlation coefficient was used to assess correlations between functional imaging parameters. Results: The ratio of PET-derived SUVmean and diffusion-weighted imaging-derived minimum ADC was introduced as a combined variable to predict tumor grade, outperforming single predictors. On the basis of a threshold ratio of 0.03, tumors could be classified as grade 2 with a sensitivity of 86% and a specificity of 100%. SUV and functional ADCs, as well as arterial contrast enhancement parameters, showed nonsignificant and mostly negligible correlations. Conclusion: Because receptor density and tumor cellularity appear to be independent, potentially complementary phenomena, the combined ratio of PET/MRI and SUVmean/ADCmin may be used as a novel biomarker allowing differentiation between grade 1 and grade 2 GEP NETs.

Facing the challenges in human resources for humanitarian health.

The human resources crisis in humanitarian health care parallels that seen in the broader area of health care. This crisis is exacerbated by the lack of resources in areas in which humanitarian action is needed--difficult environments that often are remote and insecure--and the requirement of specific skill sets is not routinely gained during traditional medical training. While there is ample data to suggest that health outcomes improve when worker density is increased, this remains an area of critical under-investment in humanitarian health care. In addition to under-investment, other factors limit the availability of human resources for health (HRH) in humanitarian work including: (1) over-reliance on degrees as surrogates for specific competencies; (2) under-development and under-utilization of national staff and beneficiaries as humanitarian health workers; (3) lack of standardized training modules to ensure adequate preparation for work in complex emergencies; (4) and the draining of limited available HRH from countries with low prevalence and high need to wealthier, developed nations also facing HRH shortages. A working group of humanitarian health experts from implementing agencies, United Nations agencies, private and governmental financiers, and members of academia gathered at Hanover, New Hampshire for a conference to discuss elements of the HRH problem in humanitarian health care and how to solve them. Several key elements of successful solutions were highlighted, including: (1) the need to develop a set of standards of what would constitute "adequate training" for humanitarian health work; (2) increasing the utilization and professional development of national staff; (3) "training with a purpose" specific to humanitarian health work (not simply relying on professional degrees as surrogates); (4) and developing specific health task-based competencies thereby increasing the pool of potential workers. Such steps would accomplish several key goals, such as: (1) more confidently ensuring that individuals hired for a given post would have the capacity to function at a commonly understood level of training; (2) greatly increasing the potential number and types of workers available for humanitarian work; (3) increasing the efficiency of human resources utilization in humanitarian projects; and (4) recognition that humanitarian work is a multi-disciplinary endeavor: these goals will contribute to ensuring that humanitarian health workers have a minimum training in broader humanitarian action, making them more effective team members in the field. Efforts were made to highlight some promising pilot programs for human resource development in humanitarian work, to identify a future vision for humanitarian health as a profession, and to develop a human resources strategy for achieving that vision.

Reforming the oversight of multi-site clinical research: a review of two possible solutions.

The current system for the ethical oversight of clinical research suffers from structural, procedural, and performance assessment problems. Initially conceived primarily to handle local investigator-initiated single-site studies, the system of institutionally-based committee review has become progressively more inefficient given the increased prevalence of commercially or federally sponsored multi-center trials. To date, proposed solutions do not adequately address these problems. Beginning with a review of these structural, procedural, and performance assessment problems, this article will then consider two proposals for addressing these deficiencies: (a) regional ethics organizations; and (b) IRBNet, a newly developed web-based program for cooperative IRB review. The strengths and weaknesses of these two approaches will be evaluated in light of recent experience with centralized review. The proposal to establish a system of regional ethics organizations presents a comprehensive approach to many of the problems faced by the current system. However, IRBNet offers an immediate and feasible solution to many of the problems faced by the review of multi-site clinical studies.

Estimating metazoan divergence times with a molecular clock.

Accurately dating when the first bilaterally symmetrical animals arose is crucial to our understanding of early animal evolution. The earliest unequivocally bilaterian fossils are approximately 555 million years old. In contrast, molecular-clock analyses calibrated by using the fossil record of vertebrates estimate that vertebrates split from dipterans (Drosophila) approximately 900 million years ago (Ma). Nonetheless, comparative genomic analyses suggest that a significant rate difference exists between vertebrates and dipterans, because the percentage difference between the genomes of mosquito and fly is greater than between fish and mouse, even though the vertebrate divergence is almost twice that of the dipteran. Here we show that the dipteran rate of molecular evolution is similar to other invertebrate taxa (echinoderms and bivalve molluscs) but not to vertebrates, which significantly decreased their rate of molecular evolution with respect to invertebrates. Using a data set consisting of the concatenation of seven different amino acid sequences from 23 ingroup taxa (giving a total of 11 different invertebrate calibration points scattered throughout the bilaterian tree and across the Phanerozoic), we estimate that the last common ancestor of bilaterians arose somewhere between 573 and 656 Ma, depending on the value assigned to the parameter scaling molecular substitution rate heterogeneity. These results are in accord with the known fossil record and support the view that the Cambrian explosion reflects, in part, the diversification of bilaterian phyla.