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We previously identified two new agents based on the [99mTcVO]3+ core with renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35- = penta-anion of mercaptoacetyltriglycine). However, renal agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2- (NTA3- = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[ReI(CO)3(NTA)]2- with a -CH2CO2- dangling monoanionic chain and on two fac-[ReI(CO)3(L)]- analogues with either a -CH2CONH2 or a -CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n- complexes, the fac-[ReI(CO)3(N(CH2CO2)2)]- moiety is structurally similar and has similar electronic properties (as assessed by NMR data). In reported and ongoing studies, the two fac-[99mTcI(CO)3(L)]- analogues with these neutral dangling chains were found to have pharmacokinetic properties very similar to those of fac-[99mTcI(CO)3(NTA)]2-. Therefore, we reach the unexpected conclusion that in fac-[99mTcI(CO)3(L)]n- agents, renal clearance is affected much more than anticipated by features of the core plus the chelate rings (the [99mTcI(CO)3(N(CH2CO2)2)]- moiety) than by the presence of a negatively charged dangling carboxylate chain. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Renal scintigraphy is an important imaging modality for the diagnosis and management of a variety of renal diseases including obstruction and renovascular hypertension as well as the evaluation of absolute and relative kidney function. The goal of this work was to evaluate Al18F-NODA-butyric acid (Al18F-1) as a potential PET tracer to image the kidneys and monitor renal function by comparing its pharmacokinetic properties with those of 131I-o-iodohippurate (131I-OIH), the radioactive standard for the measurement of effective renal plasma flow. Methods: Al18F-1 was prepared in aqueous conditions using a one-pot Al18F-radiofluorination method and its radiochemical purity was determined by HPLC. Biodistribution studies, using 131I-OIH as an internal control, were performed in normal rats and in rats with renal pedicle ligation. In vitro stability and metabolism of Al18F-1 were analyzed by HPLC. Dynamic microPET/CT studies were conducted in normal rats. Results: Al18F-1 showed excellent stability in vitro and in vivo. Biodistribution studies in normal rats and in rats with simulated renal failure confirmed that Al18F-1 was exclusively cleared through the renal–urinary pathway and that the hepatic/gastrointestinal activity was less for Al18F-1 than for 131I-OIH both at 10 and 60min. Dynamic PET showed a rapid transit of Al18F-1 through the kidneys into the bladder. Conclusion: These results suggest that the easily labeled Al18F-based compounds provide a highly promising approach for the development of a PET renal radiotracer that combines superior imaging qualities with a reliable measure of effective renal plasma flow. [Copyright &y& Elsevier]

Abstract: Introduction: The first human studies of a characterized radiopharmaceutical containing a {99mTc(CO)3}+ core, Na[99mTc(CO)3(LAN)], demonstrated that Na[99mTc(CO)3(LAN)] was an excellent renal imaging agent; however, its clearance was less than that of 131I-orthoiodohippurate (131I-OIH), and it did not provide a direct measure of effective renal plasma flow. In order to develop a 99mTc renal agent with pharmacokinetic properties equivalent to those of 131I-OIH, we investigated the 99mTc(CO)3/Re(CO)3 complexes formed from carboxymethylmercaptosuccinic acid (CMSAH3) and thiodisuccinic acid (TDSAH4). Once the ligand is bound to 99mTc(CO)3 through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the renal tubular transporter. Methods: X-ray crystal structural analysis of [NMe4][Re(CO)3(CMSAH)] was performed to interpret the nature of 99mTc tracers. CMSAH3 and TDSAH4 were radiolabeled by incubating each ligand and the precursor [99mTc(CO)3(H2O)3]+ at 70°C (pH 7) for 30 min. The products were purified by reversed-phase high-performance liquid chromatography, and biodistribution studies were performed in Sprague–Dawley rats, with 131I-OIH as an internal control at 10 and 60 min. Results: Radiolabeling CMSAH3 and TDSAH4 with the [99mTc(CO)3(H2O)3]+ precursor gave products quantitatively. Analysis of the Re(CO)3 complexes with the CMSAH3 and TDSAH4 ligands demonstrates that ligands are bound in 99mTc/Re(CO)3 complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two 5-membered chelate rings). Renal excretion at 60 min (activity in the urine as a percentage of 131I-OIH) was 68±1% for Na3[99mTc(CO)3(TDSA)] but was 98±1% for Na2[99mTc(CO)3(CMSA)]. Conclusion: In rats, Na2[99mTc(CO)3(CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as 131I-OIH; consequently, Na2[99mTc(CO)3(CMSA)] may provide a direct measure of effective renal plasma flow, and further evaluation in humans is warranted. [Copyright &y& Elsevier]

Two new N2S2 ligands [S-trityl-l-cysteine-acetamide-ethanethiol ethyl ester (Tr-l-CAATH2-Et, 1) and S-trityl-d-penicillamine-acetamide-(2-methyl-2-propanethiol) ethyl ester (Tr-d-TMCAATH2-Et, 2)] were prepared. These ligands, with the electron-withdrawing carboxyl group separated by only two bonds from the NH amine group, belong to monoamide-monoamine-dithiol (MAMA) class of chelates that typically form M(V)O(N2S2) (M=Tc, Re) complexes with the ligand secondary amine pKa of ∼6–7 and both syn and anti isomers. Re(V)O(N2S2) complexes were prepared from 1 and 2 with the dangling ester either syn or anti to the Re&z.dbnd6;O intact or hydrolyzed; the latter, ReO(l-CAATH2) and ReO(d-TMCAATH2) have a carboxyl group needed for renal imaging when M=Tc. The gross structure of syn-ReO(l-CAATH-Et) (3) is typical of Re(V)O(N2S2) complexes. However, within the cys moiety of 3, an intramolecular H-bond between the ester carbonyl oxygen O(4) and the NH (N(2)⋯O(4) distance=2.80 A˚) causes the cys chelate ring to adopt an unusual conformation with the αC (C(5)) atom 0.42 A˚ below the plane defined by the cys S, Re, and N(2) atoms with respect to the Re&z.dbnd6;O group. From molecular mechanics (MM) analysis of ReO(l-CAATH2) models, the lowest-energy syn-ReO(l-CAATH2) structure has a corresponding region similar to that of the X-ray structure for 3, an N(2)H endo with respect to Re&z.dbnd6;O group, a N(2)H⋯O(4) hydrogen bond (2.69 A˚ N(2)⋯O(4) distance) contributing ∼5 kcal mol−1 to its stability and an αC atom deviating 0.24 A˚ from the cys S, Re, and N(2) plane. Computed structures with an exo N(2)H are ∼6 kcal mol−1 less stable than the lowest-energy endo analogue. Below pH ∼7, the 1H NMR spectrum of syn-ReO(d-TMCAATH2) exhibited changes in two pH regions, consistent with sequential protonation of the amine and of the carboxylic group. These experimental and MM results reinforce previous hypotheses about the factors favoring one syn form in one ionization state of M(V)O(N2S2) compounds at physiological pH. [Copyright &y& Elsevier]

Fishing in Oklahoma's rivers and streams provides a unique experience for anglers in the state. Despite its popularity, information on total demand and economic benefits associated with stream fishing is limited in the state. Research on the role of site quality indicators, such as fish size and quantity, on recreational fishing has shown mixed results. Whether fish size or quantity plays an important role in determining fishing demand and economic value may have important management implications. We estimated the demand and economic value of fishing under varying scenarios by using anglers' responses to hypothetical behavioral questions related to fishing in Ozark Highland streams and rivers in Oklahoma. We asked how intended number of trips might change in the future given hypothetical increases in catch rates of fish, catch rates of trophy-sized fish, and catch rates of preferred fish species, in combination with anglers' trip-related data. Under current conditions, we estimated consumer surplus per person per trip to be $55 and aggregate value across all stream anglers in Oklahoma to be $68.51 million. Changes in marginal benefits varied among hypothetical scenarios of fish size and abundance but was maximized with a 25% increase in catch rates of trophy-sized fish. The study findings contribute to the understanding of the economic benefit of fishing in streams and suggest that fish size, rather than fish quantity, is more important to stream anglers in the area. • Little is known about economic benefits associate with stream fishing in Oklahoma. • Past research on the role of fish size and quantity on fishing demand and economic value has shown mixed results. • A travel cost and contingent behavior models were estimated for recreation fishing in Oklahoma streams and rivers. • Results illustrate huge economic benefits of fishing in Oklahoma streams and rivers. • We found that increase in fish size and quantity increase fishing demand and economic value. [ABSTRACT FROM AUTHOR]

Radionuclide imaging plays a critical role in the diagnosis and management of kidney obstruction. However, most practicing radiologists in US hospitals have insufficient time and resources to acquire training and experience needed to interpret radionuclide images, leading to increased diagnostic errors. To tackle this problem, Emory University embarked on a study that aims to develop a computer-assisted diagnostic (CAD) tool for kidney obstruction by mining and analyzing patient data comprised of renogram curves, ordinal expert ratings on the obstruction status, pharmacokinetic variables, and demographic information. The major challenges here are the heterogeneity in data modes and the lack of gold standard for determining kidney obstruction. In this article, we develop a statistically principled CAD tool based on an integrative latent class model that leverages heterogeneous data modalities available for each patient to provide accurate prediction of kidney obstruction. Our integrative model consists of three sub-models (multilevel functional latent factor regression model, probit scalar-on-function regression model, and Gaussian mixture model), each of which is tailored to the specific data mode and depends on the unknown obstruction status (latent class). An efficient MCMC algorithm is developed to train the model and predict kidney obstruction with associated uncertainty. Extensive simulations are conducted to evaluate the performance of the proposed method. An application to an Emory renal study demonstrates the usefulness of our model as a CAD tool for kidney obstruction., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. [br]For permissions, please e-mail: journals.permissions@oup.com.)

Objective: iRENEX is a software module that incorporates scintigraphic and clinical data to interpret 99m Tc- mercaptoacetyltriglycine (MAG3) diuretic studies and provide reasons for their conclusions. Our objectives were to compare iRENEX interpretations with those of expert physicians, use iRENEX to evaluate resident performance and determine if iRENEX could improve the diagnostic accuracy of experienced residents., Methods: Baseline and furosemide 99m Tc-MAG3 acquisitions of 50 patients with suspected obstruction (mean age ± SD, 58.7 ± 15.8 years, 60% female) were randomly selected from an archived database and independently interpreted by iRENEX, three expert readers and four nuclear medicine residents with one full year of residency. All raters had access to scintigraphic data and a text file containing clinical information and scored each kidney on a scale from +1.0 to -1.0. Scores ≥0.20 represented obstruction with higher scores indicating greater confidence. Scores +0.19 to -0.19 were indeterminate; scores ≤-0.20 indicated no obstruction. Several months later, residents reinterpreted the studies with access to iRENEX. Receiver operating characteristic (ROC) analysis and concordance correlation coefficient (CCC) quantified agreement., Results: The CCC among experts was higher than that among residents, 0.84, versus 0.39, respectively, P  < 0.001. When residents reinterpreted the studies with iRENEX, their CCC improved from 0.39 to 0.73, P  < 0.001. ROC analysis showed significant improvement in the ability of residents to distinguish between obstructed and non-obstructed kidneys using iRENEX ( P  = 0.036)., Conclusion: iRENEX interpretations were comparable to those of experts. iRENEX reduced interobserver variability among experienced residents and led to better agreement between resident and expert interpretations., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The Neosho Bass ( Micropterus velox ), a former subspecies of the keystone top-predator and globally popular Smallmouth Bass ( M. dolomieu ), is endemic and narrowly restricted to small, clear streams of the Arkansas River Basin in the Central Interior Highlands (CIH) ecoregion, USA. Previous studies have detected some morphological, genetic, and genomic differentiation between the Neosho and Smallmouth Basses; however, the extent of neutral and adaptive divergence and patterns of intraspecific diversity are poorly understood. Furthermore, lineage diversification has likely been impacted by gene flow in some Neosho populations, which may be due to a combination of natural biogeographic processes and anthropogenic introductions. We assessed: (1) lineage divergence, (2) local directional selection (adaptive divergence), and (3) demographic history among Smallmouth Bass populations in the CIH using population genomic analyses of 50,828 single-nucleotide polymorphisms (SNPs) obtained through ddRAD-seq. Neosho and Smallmouth Bass formed monophyletic clades with 100% bootstrap support. We identified two major lineages within each species. We discovered six Neosho Bass populations (two nonadmixed and four admixed) and three nonadmixed Smallmouth Bass populations. We detected 29 SNPs putatively under directional selection in the Neosho range, suggesting populations may be locally adapted. Two populations were admixed via recent asymmetric secondary contact, perhaps after anthropogenic introduction. Two other populations were likely admixed via combinations of ancient and recent processes. These species comprise independently evolving lineages, some having experienced historical and natural admixture. These results may be critical for management of Neosho Bass as a distinct species and may aid in the conservation of other species with complex biogeographic histories., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Informed management and conservation efforts are vital to sustainable recreational fishing and biodiversity conservation. Because the taxonomic rank of species is important in conservation and management strategies, success of these efforts depends on accurate species delimitation. The Black Basses (Micropterus) are an iconic lineage of freshwater fishes that include some of the world's most popular species for recreational fishing and world's most invasive species. Despite their popularity, previous studies to delimit species and lineages in Micropterus suffer from insufficient geographic coverage and uninformative molecular markers. Our phylogenomic analyses of ddRAD data result in the delimitation of 19 species of Micropterus, which includes 14 described species, the undescribed but well-known Altamaha, Bartram's, and Choctaw basses, and two additional undescribed species currently classified as Smallmouth Bass (M. dolomieu). We provide a revised delimitation of species in the Largemouth Bass complex that necessitates a change in scientific nomenclature: Micropterus salmoides is retained for the Florida Bass and Micropterus nigricans is elevated from synonymy for the Largemouth Bass. The new understanding of diversity, distribution, and systematics of Black Basses will serve as important basis for the management and conservation of this charismatic and economically important clade of fishes., (© 2022. The Author(s).)

Purpose: 99m Tc-tricarbonyl-nitrilotriacetic acid, [ 99m Tc]Tc(CO) 3 (NTA), is a new 99m Tc-renal radiopharmaceutical with a clearance equal to that of 131 I-ortho-iodohippuran, [ 131 I]I-OIH. Our purpose was to compare the performance of [ 99m Tc]Tc(CO) 3 (NTA) and [ 99m Tc]Tc-MAG3 in patients with suspected obstruction., Methods: [ 99m Tc]Tc(CO) 3 (NTA) was prepared with commercially available NTA ligand and CRS Isolink kit, and isolated by HPLC. Eighteen adult patients referred for diuretic renography received an intravenous injection of approximately 40 mg of furosemide 15 min prior to either [ 99m Tc]Tc(CO) 3 (NTA) or [ 99m Tc]Tc-MAG3 (mean activity of 47 ± 4.4 MBq). Data were acquired for 24 min followed by an anterior image of the liver and gall bladder and a measure of voided volume. Patients received a second furosemide injection equal to one third of the original dose followed fifteen minutes later by administration of the alternate tracer, mean activity of 320 ± 34 MBq. Clearances were measured using a camera-based technique., Results: The clearance of NTA was greater than that of MAG3, 331 ± 146 versus 271 ± 105 mL/min/1.73 m 2 , respectively, p < 0.0001. The kidney to background ratio for NTA was greater than that of MAG3 for both left and right kidneys, p < 0.001; the 20 min/maximum count ratio was significantly less, p < 0.0001. There was no significant difference in the voiding volumes following NTA and MAG3 administration, 598 ± 237 mL versus 498 ± 170 mL, respectively, p = 0.07. Gall bladder activity was not observed with NTA but was present in 6/17 MAG3 studies. Images and renogram curves were comparable except for two patients where the NTA study excluded obstruction but the MAG3 study suggested an indeterminate or obstructed kidney., Conclusions: Unlike MAG3, NTA is not eliminated via the hepatobiliary track. Moreover, NTA has a higher kidney to background ratio and more rapid clearance than MAG3. These advantages should allow more robust camera-based clearance measurements and may lead to better discrimination between obstructed and non-obstructed kidneys.

Kidney obstruction, if untreated in a timely manner, can lead to irreversible loss of renal function. A widely used technology for evaluations of kidneys with suspected obstruction is diuresis renography. However, it is generally very challenging for radiologists who typically interpret renography data in practice to build high level of competency due to the low volume of renography studies and insufficient training. Another challenge is that there is currently no gold standard for detection of kidney obstruction. Seeking to develop a computer-aided diagnostic (CAD) tool that can assist practicing radiologists to reduce errors in the interpretation of kidney obstruction, a recent study collected data from diuresis renography, interpretations on the renography data from highly experienced nuclear medicine experts as well as clinical data. To achieve the objective, we develop a statistical model that can be used as a CAD tool for assisting radiologists in kidney interpretation. We use a Bayesian latent class modeling approach for predicting kidney obstruction through the integrative analysis of time-series renogram data, expert ratings, and clinical variables. A nonparametric Bayesian latent factor regression approach is adopted for modeling renogram curves in which the coefficients of the basis functions are parameterized via the factor loadings dependent on the latent disease status and the extended latent factors that can also adjust for clinical variables. A hierarchical probit model is used for expert ratings, allowing for training with rating data from multiple experts while predicting with at most one expert, which makes the proposed model operable in practice. An efficient MCMC algorithm is developed to train the model and predict kidney obstruction with associated uncertainty. We demonstrate the superiority of the proposed method over several existing methods through extensive simulations. Analysis of the renal study also lends support to the usefulness of our model as a CAD tool to assist less experienced radiologists in the field.

Leveraging existing presence records and geospatial datasets, species distribution modeling has been widely applied to informing species conservation and restoration efforts. Maxent is one of the most popular modeling algorithms, yet recent research has demonstrated Maxent models are vulnerable to prediction errors related to spatial sampling bias and model complexity. Despite elevated rates of biodiversity imperilment in stream ecosystems, the application of Maxent models to stream networks has lagged, as has the availability of tools to address potential sources of error and calculate model evaluation metrics when modeling in nonraster environments (such as stream networks). Herein, we use Maxent and customized R code to estimate the potential distribution of paddlefish ( Polyodon spathula ) at a stream-segment level within the Arkansas River basin, USA, while accounting for potential spatial sampling bias and model complexity. Filtering the presence data appeared to adequately remove an eastward, large-river sampling bias that was evident within the unfiltered presence dataset. In particular, our novel riverscape filter provided a repeatable means of obtaining a relatively even coverage of presence data among watersheds and streams of varying sizes. The greatest differences in estimated distributions were observed among models constructed with default versus AIC C -selected parameterization. Although all models had similarly high performance and evaluation metrics, the AIC C -selected models were more inclusive of westward-situated and smaller, headwater streams. Overall, our results solidified the importance of accounting for model complexity and spatial sampling bias in SDMs constructed within stream networks and provided a roadmap for future paddlefish restoration efforts in the study area., Competing Interests: The authors declare they have no conflict of interest., (© 2019 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Ligands that coordinate via dianionic phosphonate groups have not been widely utilized in radiopharmaceuticals. N -(phosphonomethyl)iminodiacetic acid ( 1 , PMIDA) and N- (phosphonomethyl)glycine ( 2 , PMG) were investigated as new chelators for the 99m Tc/Re-tricarbonyl "core" ( fac -M(CO) 3 , M = 99m Tc, Re) present in a major class of radiopharmaceuticals. fac-M(CO) 3 (PMIDA) and fac-M(CO) 3 (PMG) complexes were studied by HPLC and 1 H/ 13 C/ 31 P NMR methods for M = Re ( Re-1 and Re-2 ) and by HPLC for M = 99m Tc ( 99m Tc-1 and 99m Tc-2 ). Re-1 and 99m Tc-1 complexes exhibit a similar pH-dependent equilibrium between geometric linkage isomers ( M-1a and M-1b ). However, only one isomer exists for M-2 under all conditions. Structural characterization by X-ray crystallography reveals the presence of a bond between a phosphonate oxygen and the Re(I) center in fac- Re(CO) 3 (PMG) ( Re-2 ). Detailed comparisons of NMR data for Re-2 conclusively demonstrate that the phosphonate group is coordinated in Re-1b (isomer favored at high pH) but not in Re-1a , which has a dangling N -(phosphonomethyl) group. To our knowledge, Re-1b and Re-2 and their 99m Tc analogs are the first well-documented examples of complexes with these metal-tricarbonyl cores having a dianionic phosphonate group directly coordinated in a fac -M(CO) 3 -O-P grouping. Pharmacokinetic studies using Sprague-Dawley rats reveal that 99m Tc-2 is a robust tracer. Hence, phosphonate groups should be considered in designing 99m Tc and 186/188 Re radiopharmaceuticals, including agents with bioactive moieties attached to dangling carboxylate or phosphonate groups.

The need to assess agreement exists in various clinical studies where quantifying inter-rater reliability is of great importance. Use of unscaled agreement indices, such as total deviation index and coverage probability (CP), is recommended for two main reasons: (i) they are intuitive in a sense that interpretations are tied to the original measurement unit; (ii) practitioners can readily determine whether the agreement is satisfactory by directly comparing the value of the index to a prespecified tolerable CP or absolute difference. However, the unscaled indices were only defined in the context of comparing two raters or multiple raters that assume homogeneity of variances across raters. In this paper, we introduce a set of overall indices based on the root mean square of pairwise differences that are unscaled and can be used to evaluate agreement among multiple raters that often exhibit heterogeneous measurement processes in practice. Furthermore, we propose another overall agreement index based on the root mean square of pairwise differences that is scaled and extends the concept of the recently proposed relative area under CP curve in the presence of multiple raters. We present the definitions of overall indices and propose inference procedures in which bootstrap methods are used for the estimation of standard errors. We assess the performance of the proposed approach and demonstrate its superiority over the existing methods when raters exhibit heterogeneous measurement processes using simulation studies. Finally, we demonstrate the application of our methods using a renal study., (© 2018 John Wiley & Sons, Ltd.)

Introduction: Our previous work demonstrated that the 99m Tc renal tracer, 99m Tc(CO) 3 (FEDA) ( 99m Tc-1), has a rapid clearance comparable in rats to that of 131 I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of 99m Tc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl 18 F renal imaging agent, Re(CO) 3 ([ 18 F]FEDA) ( 18 F-1). Our goal was to develop an efficient one-step method for the preparation of 18 F-1 and to compare its pharmacokinetic properties with those of 131 I-OIH in rats., Methods: 18 F-1 was prepared by the nucleophilic 18 F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and subsequently evaluated in Sprague-Dawley rats using 131 I-OIH as an internal control and by dynamic PET/CT imaging. Plasma protein binding (PPB) and erythrocyte uptake (RCB) were determined and the urine was analyzed for metabolites., Results: 18 F-1 was efficiently prepared as a single species with high radiochemical purity (>99%) and it displayed high radiochemical stability in vitro and in vivo. PPB was 87% and RCB was 21%. Biodistribution studies confirmed rapid renal extraction and high specificity for renal excretion, comparable to that of 131 I-OIH, with minimal hepatic/gastrointestinal elimination. The activity in the urine, as a percentage of 131 I-OIH, was 92% and 95% at 10 and 60 min, respectively. All other organs (heart, spleen, lungs) showed a negligible tracer uptake (<0.4% ID). Dynamic microPET/CT imaging demonstrated rapid transit of 18 F-1 through the kidneys and into the bladder; there was no demonstrable activity in bone verifying the absence of free [ 18 F]fluoride., Conclusions: 18 F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of 131 I-OIH and high in vivo radiochemical stability. Not only is 18 F-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous 18 F/ 99m Tc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Fluvial fishes face increased imperilment from anthropogenic activities, but the specific factors contributing most to range declines are often poorly understood. For example, the range of the fluvial-specialist shoal bass (Micropterus cataractae) continues to decrease, yet how perceived threats have contributed to range loss is largely unknown. We used species distribution models to determine which factors contributed most to shoal bass range loss. We estimated a potential distribution based on natural abiotic factors and a series of currently occupied distributions that incorporated variables characterizing land cover, non-native species, and river fragmentation intensity (no fragmentation, dams only, and dams and large impoundments). We allowed interspecific relationships between non-native congeners and shoal bass to vary across fragmentation intensities. Results from the potential distribution model estimated shoal bass presence throughout much of their native basin, whereas models of currently occupied distribution showed that range loss increased as fragmentation intensified. Response curves from models of currently occupied distribution indicated a potential interaction between fragmentation intensity and the relationship between shoal bass and non-native congeners, wherein non-natives may be favored at the highest fragmentation intensity. Response curves also suggested that >100 km of interconnected, free-flowing stream fragments were necessary to support shoal bass presence. Model evaluation, including an independent validation, suggested that models had favorable predictive and discriminative abilities. Similar approaches that use readily available, diverse, geospatial data sets may deliver insights into the biology and conservation needs of other fluvial species facing similar threats., (© 2017 Society for Conservation Biology.)

Purpose To determine if commonly administered doses of technetium 99m ( 99m Tc) mertiatide (MAG 3 ) in the range of 300-370 MBq (approximately 8-10 mCi) contribute to image interpretation and justify the resulting radiation exposure. Materials and Methods The respective institutional review boards approved this HIPAA-compliant study and waived informed consent. Baseline and furosemide 99m Tc-MAG 3 imaging examinations in 50 patients suspected of having renal obstruction and 48 patients suspected of having renovascular hypertension (RVH) were randomly selected from archived databases and were independently scored by three experienced readers without access to 2-second flow images. Readers were blinded to their original scores, and then they rescored each examination with access to high-activity 2-second flow images. Relative renal function was determined after a low activity (62.9 MBq ± 40.7) baseline acquisition for RVH and a high activity (303.4 MBq ± 48.1) acquisition after administration of enalaprilat. Data were analyzed by using random effects analysis of variance and mean and standard error of the mean for the difference between sets of scores and the difference between relative function measurements. Results There was no significant difference in the scores without flow images compared with blinded scores with high-activity flow images for patients suspected of having obstruction (P = .80) or RVH (P = .24). Moreover, there was no significant difference in the relative uptake measurements after administration of low and high activities (P > .99). Conclusion Administered doses of 99m Tc-MAG 3 in the range of 300-370 MBq (approximately 8-10 mCi) do not affect the relative function measurements or contribute to interpretation of images in patients suspected of having RVH or obstruction compared with administration of lower doses; unnecessary radiation exposure can be avoided by administering doses in the range of 37-185 MBq as recommended incurrent guidelines. © RSNA, 2017.

To develop the first radiotracer targeting GPR91, a cell membrane-bound receptor that modulates the cellular response to hyperglycemia and hypoxia, we designed and prepared a small series of compounds based on a published series of 1,8-naphthyridines with high affinity to GPR91. Our approach provides a mechanism to incorporate radioactive atoms ((99m)Tc and (18)F) into the GPR91 pharmacophore as the final synthetic step. Pharmacological assays confirmed lead compounds for (99m)Tc and (18)F GPR91 radiotracers within the series., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Preclinical studies in rats showed that two of (99m)Tc(CO)3(ASMA) isomers (rac- and L-ASMA) had pharmacokinetic properties equivalent to that of (131)I-OIH, the radiopharmaceutical standard for the measurement of effective renal plasma flow. The aim of this study was to evaluate the pharmacokinetics of (99m)Tc(CO)3(ASMA) isomers in healthy human subjects., Methods: Three ASMA ligands (rac-, L- and D-ASMA) were labeled with (99m)Tc(CO)3 using an IsoLink kit (Covidien), and each formed (99m)Tc(CO)3(ASMA) tracer was co-injected with (131)I-OIH into healthy human subjects followed by sequential imaging, plasma clearance measurements and timed urine collection. Plasma protein binding, red cell uptake and percent injected dose in the urine were determined. Urine from each group of volunteers was analyzed for metabolites by HPLC., Results: Image quality was excellent with all three agents. Each (99m)Tc(CO)3(ASMA) preparation was excreted unchanged in the urine. The plasma clearance ratio ((99m)Tc(CO)3(ASMA)/(131)I-OIH) was 81 ± 3 % for D-ASMA compared to only 20 ± 4 % for L-ASMA and 37 ± 7 % for rac-ASMA; the 81 % clearance ratio for D-ASMA isomer is still ∼ 30 % higher than the (99m)Tc-MAG3/(131)I-OIH clearance ratio (∼50-60 %). Red cell uptake was similar for all three tracers (6-9 %), and all tracers had a relatively rapid renal excretion; at 3 h, the (99m)Tc(CO)3(ASMA)/(131)I-OIH urine ratio was 100 ± 3 % for D-ASMA, 80 ± 2 % for L-ASMA and 88 ± 1 % for rac-ASMA., Conclusions: The renal excretion characteristics of (99m)Tc(CO)3(D-ASMA) in humans are superior to those of the other two (99m)Tc(CO)3(ASMA) isomers studied, but are still inferior to (131)I-OIH, even though there was no difference in the clearance of two of (99m)Tc(CO)3(ASMA) isomers and (131)I-OIH in rats. The work described here demonstrates the sensitivity in in vivo biological behavior of (99m)Tc(CO)3(ASMA) isomers to their subtle structural differences.

Diagnostic imaging is becoming more complicated, physicians are also required to master an ever-expanding knowledge base and take into account an ever increasing amount of patient-specific clinical information while the time available to master this knowledge base, assemble the relevant clinical data, and apply it to specific tasks is steadily shrinking. Compounding these problems, there is an ever increasing number of aging "Baby Boomers" who are becoming patients coupled with a declining number of cardiac diagnosticians experienced in interpreting these studies. Hence, it is crucial that decision support tools be developed and implemented to assist physicians in interpreting studies at a faster rate and at the highest level of up-to-date expertise. Such tools will minimize subjectivity and intra- and inter-observer variation in image interpretation, help achieve a standardized high level of performance, and reduce healthcare costs. Presently, there are many decision support systems and approaches being developed and implemented to provide greater automation and to further objectify and standardize analysis, display, integration, interpretation, and reporting of myocardial perfusion SPECT and PET studies. This review focuses on these systems and approaches.

The goal of artificial intelligence, expert systems, decision support systems, and computer-assisted diagnosis (CAD) in imaging is the development and implementation of software to assist in the detection and evaluation of abnormalities, to alert physicians to cognitive biases, to reduce intraobserver and interobserver variability, and to facilitate the interpretation of studies at a faster rate and with a higher level of accuracy. These developments are needed to meet the challenges resulting from a rapid increase in the volume of diagnostic imaging studies coupled with a concurrent increase in the number and complexity of images in each patient data. The convergence of an expanding knowledge base and escalating time constraints increases the likelihood of physician errors. Errors are even more likely when physicians interpret low-volume studies such as technetium-99m-mercaptoacetyltriglycine diuretic scans where imagers may have had limited training or experience. Decision support systems include neural networks, case-based reasoning, expert systems, and statistical systems. iRENEX (renal expert) is an expert system for diuretic renography that uses a set of rules obtained from human experts to analyze a knowledge base of both clinical parameters and quantitative parameters derived from the renogram. Initial studies have shown that the interpretations provided by iRENEX are comparable to the interpretations of a panel of experts. iRENEX provides immediate patient-specific feedback at the time of scan interpretation, can be queried to provide the reasons for its conclusions, and can be used as an educational tool to teach trainees to better interpret renal scans. It also has the capacity to populate a structured reporting module and generate a clear and concise impression based on the elements contained in the report; adherence to the procedural and data entry components of the structured reporting module ensures and documents procedural competency. Finally, although the focus is CAD applied to diuretic renography, this review offers a window into the rationale, methodology, and broader applications of computer-assisted diagnosis in medical imaging., (© 2013 Published by Elsevier Inc.)

Introduction: Renal scintigraphy is an important imaging modality for the diagnosis and management of a variety of renal diseases including obstruction and renovascular hypertension as well as the evaluation of absolute and relative kidney function. The goal of this work was to evaluate Al(18)F-NODA-butyric acid (Al(18)F-1) as a potential PET tracer to image the kidneys and monitor renal function by comparing its pharmacokinetic properties with those of (131)I-o-iodohippurate ((131)I-OIH), the radioactive standard for the measurement of effective renal plasma flow., Methods: Al(18)F-1 was prepared in aqueous conditions using a one-pot Al(18)F-radiofluorination method and its radiochemical purity was determined by HPLC. Biodistribution studies, using (131)I-OIH as an internal control, were performed in normal rats and in rats with renal pedicle ligation. In vitro stability and metabolism of Al(18)F-1 were analyzed by HPLC. Dynamic microPET/CT studies were conducted in normal rats., Results: Al(18)F-1 showed excellent stability in vitro and in vivo. Biodistribution studies in normal rats and in rats with simulated renal failure confirmed that Al(18)F-1 was exclusively cleared through the renal-urinary pathway and that the hepatic/gastrointestinal activity was less for Al(18)F-1 than for (131)I-OIH both at 10 and 60 min. Dynamic PET showed a rapid transit of Al(18)F-1 through the kidneys into the bladder., Conclusion: These results suggest that the easily labeled Al(18)F-based compounds provide a highly promising approach for the development of a PET renal radiotracer that combines superior imaging qualities with a reliable measure of effective renal plasma flow., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The reaction of an aminopolycarboxylate ligand, as partic- N - m onoacetic a cid (ASMA), with [Re(CO) 3 (H 2 O) 3 ] + was examined. The tridentate coordination of ASMA to this Re I tricarbonyl precursor yielded fac -Re(CO) 3 (ASMA) as a mixture of diastereomers. The chemistry is analogous to that of the Tc I tricarbonyl complex, which yields fac - 99m Tc(CO) 3 (ASMA) under similar conditions. The formation, structure, and isomerization of fac -Re(CO) 3 (ASMA) products were characterized by HPLC, 1 H NMR spectroscopy, and X-ray crystallography. The two major fac -Re(CO) 3 (ASMA) diastereomeric products each have a linear ONO coordination mode with two adjacent five-membered chelate rings, but they differ in the endo or exo orientation of the uncoordinated acetate group, in agreement with expectations based on previous studies. Conditions have been identified for the expedient isomerization of fac -Re(CO) 3 (ASMA) to a mixture consisting primarily of one major product. Because different isomeric species typically have different pharmacokinetic characteristics, these conditions may provide for the practical isolation of a single 99m Tc(CO) 3 (ASMA) species, thus allowing the isolation of the isomer that has optimal imaging and pharmacokinetic characteristics. This information will aid in the design of future 99m Tc radiopharmaceuticals.

This Guidance Document for structured reporting of diuresis renography in adults was developed by the International Scientific Committee of Radionuclides in Nephro-urology (ISCORN; http://www.iscorn.org). ISCORN chose diuresis renography for its first structured report Guidance Document because suspected obstruction is the most common reason for referral, most radionuclide renal studies are conducted at institutions that perform fewer than 3 studies per week, and a large percentage of studies are interpreted by physicians with limited training in nuclear medicine. Ten panelists were asked to categorize specific reporting elements as essential, recommended, optional (without sufficient data to support a higher ranking), and unnecessary (does not contribute to scan interpretation or quality assurance). The final document was developed through an iterative series of comments and questionnaires with a majority vote required to place an element in a specific category. The Guidance Document recommends a reporting structure organized into indications, clinical history, study procedure, findings and impression and specifies the elements considered essential or recommended in each category. The Guidance Document is not intended to be restrictive but, rather, to provide a basic structure and rationale so that the diuresis renography report will: (1) communicate the results to the referring physician in a clear and concise manner designed to optimize patient care; (2) contain the essential elements required to evaluate and interpret the study; (3) clearly document the technical components of the study necessary for accountability, quality assurance and reimbursement; and (4) encourage clinical research by facilitating better comparison and extrapolation of results between institutions., (Copyright © 2012. Published by Elsevier Inc.)

Objective: The purpose of this study was to facilitate interpretation of (99m)Tc-mercaptoacetyltriglycine (MAG3) diuretic scans by identifying key interpretative variables and developing a predictive model for computer-assisted diagnosis., Materials and Methods: Ninety-seven studies were randomly selected from an archived database of MAG3 baseline and furosemide acquisitions and scan interpretations (obstruction, equivocal finding, or no obstruction) derived from a consensus of three experts. Sixty-one studies (120 kidneys) were randomly chosen to build a predictive model for diagnosing or excluding obstruction. The other 36 studies (71 kidneys) composed the validation group. The probability of normal drainage (no obstruction) at the baseline acquisition and the probability of no obstruction, equivocal finding, or obstruction after furosemide administration were determined by logistic regression analysis and proportional odds modeling of MAG3 renographic data., Results: The single most important baseline variable for excluding obstruction was the ratio of postvoid counts to maximum counts. Renal counts in the last minute of furosemide acquisition divided by the maximum baseline acquisition renal counts and time to half-maximum counts after furosemide administration in a pelvic region of interest were the critical variables for determining obstruction. The area under the receiver operating characteristic curve (AUC) for predicting normal drainage in the validation sample was 0.93 (standard error, 0.02); sensitivity, 85%; specificity, 93%. The AUC for the diagnosis of obstruction after furosemide administration was 0.84 (standard error, 0.06); sensitivity, 82%; specificity, 83%., Conclusion: A predictive system has been developed that provides a promising computer-assisted diagnosis approach to the interpretation of MAG3 diuretic renal scans; this system has also identified the key variables required for scan interpretation.

BACKGROUND: The accuracy of computer-aided diagnosis (CAD) software is best evaluated by comparison to a gold standard which represents the true status of disease. In many settings, however, knowledge of the true status of disease is not possible and accuracy is evaluated against the interpretations of an expert panel. Common statistical approaches to evaluate accuracy include receiver operating characteristic (ROC) and kappa analysis but both of these methods have significant limitations and cannot answer the question of equivalence: Is the CAD performance equivalent to that of an expert? The goal of this study is to show the strength of log-linear analysis over standard ROC and kappa statistics in evaluating the accuracy of computer-aided diagnosis of renal obstruction compared to the diagnosis provided by expert readers. METHODS: Log-linear modeling was utilized to analyze a previously published database that used ROC and kappa statistics to compare diuresis renography scan interpretations (non-obstructed, equivocal, or obstructed) generated by a renal expert system (RENEX) in 185 kidneys (95 patients) with the independent and consensus scan interpretations of three experts who were blinded to clinical information and prospectively and independently graded each kidney as obstructed, equivocal, or non-obstructed. RESULTS: Log-linear modeling showed that RENEX and the expert consensus had beyond-chance agreement in both non-obstructed and obstructed readings (both p < 0.0001). Moreover, pairwise agreement between experts and pairwise agreement between each expert and RENEX were not significantly different (p = 0.41, 0.95, 0.81 for the non-obstructed, equivocal, and obstructed categories, respectively). Similarly, the three-way agreement of the three experts and three-way agreement of two experts and RENEX was not significantly different for non-obstructed (p = 0.79) and obstructed (p = 0.49) categories. CONCLUSION: Log-linear modeling showed that RENEX was equivalent to any expert in rating kidneys, particularly in the obstructed and non-obstructed categories. This conclusion, which could not be derived from the original ROC and kappa analysis, emphasizes and illustrates the role and importance of log-linear modeling in the absence of a gold standard. The log-linear analysis also provides additional evidence that RENEX has the potential to assist in the interpretation of diuresis renography studies.

We study Re analogues of (99m)Tc renal agents to interpret previous results at the (99m)Tc tracer level. The relative propensities of amine donors versus carboxylate oxygen donors of four L = polyaminocarboxylate ligands to coordinate in fac-[Re(I)(CO)(3)L](n) complexes were assessed by examining the reaction of fac-[Re(I)(CO)(3)(H(2)O)(3)](+) under conditions differing in acidity and temperature. All four L [N,N-bis-(2-aminoethyl)glycine (DTGH), N,N-ethylenediaminediacetic acid, diethylenetriamine-N-malonic acid, and diethylenetriamine-N-acetic acid] can coordinate as tridentate ligands while creating a dangling chain terminated in a carboxyl group. Dangling carboxyl groups facilitate renal clearance in fac-[(99m)Tc(I)(CO)(3)L](n) agents. Under neutral conditions, the four ligands each gave two fac-[Re(I)(CO)(3)L](n) products with HPLC traces correlating well with known traces of the fac-[(99m)Tc(I)(CO)(3)L](n) mixtures. Such mixtures are common in renal agents because the needed dangling carboxyl group can compete for a coordination site. However, the HPLC separations needed to assess the biodistribution of a single tracer are impractical in a clinical setting. One goal in investigating this Re chemistry is to identify conditions for avoiding this problem of mixtures in preparations of fac-[(99m)Tc(I)(CO)(3)L](n) renal tracers. After separation and isolation of the fac-[Re(I)(CO)(3)L](n) products, NMR analysis of all products and single crystal X-ray crystallographic analysis of both DTGH products, as well as one product each from the other L, allowed us to establish coordination mode unambiguously. The product favored in acidic conditions has a dangling amine chain and more bound oxygen. The product favored in basic conditions has a dangling carboxyl chain and more bound nitrogen. At the elevated temperatures used for simulating tracer preparation, equilibration was facile (ca. 1 h or less), allowing selective formation of one product by utilizing acidic or basic conditions. The results of this fundamental study offer protocols and guidance useful for the design and preparation of fac-[(99m)Tc(I)(CO)(3)L](n) agents consisting of a single tracer.

Unlabelled: 99mTc-Mercaptoacetyltriglycine ((99m)Tc-MAG3) and (99m)Tc-L,L-ethylenedicysteine ((99m)Tc-LL-EC) are useful renal radiopharmaceuticals; however, both agents have renal clearances less than that of (131)I-orthoiodohippurate ((131)I-OIH), and (99m)Tc-LL-EC exists in dianionic and monoanionic forms at physiologic pH. In an effort to develop a superior (99m)Tc agent with a rapid clearance comparable with that of (131)I-OIH, we have designed a new ligand system, mercaptoacetamide-ethylene-cysteine (MAEC), which combines important structural features of both MAG3 and EC., Methods: Biodistribution and clearance studies were performed on Sprague-Dawley rats using syn- and anti-(99m)Tc-L- and -D-MAEC coinjected with (131)I-OIH. Studies were also performed by coinjecting each isomer ( approximately 74 MBq [ approximately 2 mCi]) and 7.4-11.1 MBq (200-300 micro Ci) of (131)I-OIH in 3 volunteers with dual-isotope imaging performed using a camera system fitted with a high-energy collimator. Blood samples were obtained from 3 to 90 min after injection and urine samples were obtained at 30, 90, and 180 min., Results: In the rats, <10% of the injected dose remained in the blood at 10 min after injection for all isomers, and the urine dose at 60 min ranged from 84% to 99% that of (131)I-OIH. The clearances of syn- and anti-(99m)Tc-L-MAEC in the rats were higher than the clearances for the D-isomers (P

Unlabelled: Nonlinear Bayesian regression permits curve fitting to a group of subjects simultaneously rather than individually. We evaluated this approach for interpreting plasma clearance curves with the goal of reducing curve-fitting failures and dealing objectively with problem datasets that may arise in clinical settings., Methods: (99m)Tc-Diethylenetriaminepentaacetic acid plasma clearance curves from 79 subjects were analyzed. The data typically comprised 7-9 samples obtained from 5-10 to 180-240 min after injection. A 2-compartment model was fitted by Bayesian regression to yield compartmental hyperparameters V1, L21, and L12 corresponding to the volume of the compartment into which tracer was injected and the transfer rates from compartment 1 to compartment 2 and from compartment 2 to compartment 1, respectively. This also yielded a clearance estimate for each subject., Results: Estimated hyperparameters were V1 = 8.9 L, L21 = 0.026 min(-1), and L12 = 0.040 min(-1). Conventional methods led to fitting failures in 2 of the 79 subjects but there were no failures with the Bayesian method. The hyperparameters were used to calculate the glomerular filtration rate for each subject from a single plasma sample with a root-mean-square error of 7.3 mL/min, which was not significantly different from the widely used Christensen-Groth formula., Conclusion: Fewer fitting failures were encountered than with conventional methods, offering an objective means of dealing with problem data. This conceptually simple model can be used directly to calculate clearance from a single plasma sample. It requires only the 3 parameters described above, whereas the Christensen-Groth method requires 6 parameters.