Detecting androgen receptor (AR), AR variant 7 (AR-V7), prostate-specific membrane antigen (PSMA), and prostate-specific antigen (PSA) gene expression in CTCs and plasma exosome-derived cfRNA in patients with metastatic castration-resistant prostate cancer (mCRPC) by integrating the VTX-1 CTC isolation system with the QIAGEN AdnaTest.

BACKGROUND: Therapies for metastatic castration-resistant prostate cancer (mCRPC) include targeting the androgen receptor (AR) with androgen receptor inhibitors (ARIs) and prostate-specific membrane antigen (PSMA). Having the ability to detect AR, AR splice variant 7 (AR-V7), or PSMA in circulating tumor cells (CTCs) or circulating exosomal cell-free RNA (cfRNA) could be helpful to guide selection of the appropriate therapy for each individual patient. The Vortex Biosciences VTX-1 system is a label-free CTC isolation system that enables the detection of the expression of multiple genes in both CTCs and exosomal cfRNA from the same blood sample in patients with mCRPC. Detection of both AR-V7 and PSMA gene expression in both CTCs and cfRNA simultaneously has not yet been reported. METHODS: To characterize the combined VTX-1-AdnaDetect workflow, 22Rv1 cancer cells were spiked into blood from healthy donors and processed with the VTX-1 to mimic patient samples and assess performances (capture efficiency, purity, AR and AR-V7 expression). Then, we collected 19 blood samples from 16 patients with mCRPC and therapeutic resistance to androgen receptor inhibitors (ARIs). Plasma was separated and the plasma-depleted blood was processed further with the VTX-1 to collect CTCs. Both plasma exosomal cfRNA and CTCs were subsequently analyzed for AR, AR-V7, PSMA, and prostate-specific antigen (PSA) mRNA expression using the AdnaTest ProstateCancerPanel AR-V7 assay. RESULTS: AR-V7 expression could be detected in 22Rv1 cells spiked into blood from healthy volunteers as well as in CTCs and plasma-derived exosomal cfRNA from patients with mCRPC by processing blood with the VTX-1 CTC isolation system followed by the AdnaTest ProstateCancerPanel AR-V7 assay. 94.7% of patient blood samples (18/19) had detectable AR expression in either CTCs or exosomal cfRNA (16 in CTCs, 12 in cfRNA). 15.8% of the 19 patient blood samples (3/19) were found to have AR-V7-positive (AR-V7+) CTCs, one of which was also AR-V7+ in the exosomal cfRNA analysis. 42.1% of patient blood samples (8/19) were found to be PSMA positive (PSMA+): 26.3% (5/19) were PSMA+ in the CTC analysis and 31.6% (6/19) were PSMA+ in the exosomal cfRNA analysis. Of those 8 PSMA+ samples, 2 had detectable PSMA only in CTCs, and 3 had detectable PSMA only in exosomal cfRNA. CONCLUSION: VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood.

Glucagon-like peptide 1 receptor agonists in end-staged kidney disease and kidney transplantation: A narrative review.

AIMS: Glucagon-like peptide 1 receptor agonists (GLP-1RA) improve glycemic control and promote weight loss in type 2 diabetes (DM2) and obesity. We identified studies describing the metabolic benefits of GLP-1RA in end-staged kidney disease (ESKD) and kidney transplantation. DATA SYNTHESIS: We searched for randomized controlled trials (RCTs) and observational studies that investigated the metabolic benefits of GLP-1RA in ESKD and kidney transplantation. We summarized the effect of GLP-1RA on measures of obesity and glycemic control, examined adverse events, and explored adherence with therapy. In small RCTs of patients with DM2 on dialysis, liraglutide for up to 12 weeks lowered HbA1c by 0.8%, reduced time in hyperglycemia by ∼2%, lowered blood glucose by 2 mmol/L and reduced weight by 1-2 kg, compared with placebo. In prospective studies inclusive of ESKD, 12 months of semaglutide reduced HbA1c by 0.8%, and contributed to weight losses of 8 kg. In retrospective cohort studies in DM2 and kidney transplantation, 12 months of GLP-1RA lowered HbA1c by 2%, and fasting glucose by ∼3 mmol/L compared with non-use, and in some reports, weight losses of up to 4 kg were described. Gastrointestinal (GI) side effects were most commonly reported, with hypoglycemia described with GLP-1RA in hemodialysis, particularly in those using insulin. CONCLUSIONS: GLP-1RA are growing in popularity in those with DM2 and obesity. In small RCTs and observational cohort studies modest glycemic and weight benefits have been described in ESKD and transplantation, but GI side effects may limit adherence. Larger and longer term studies of GLP-1RA remain important.

The rare case of double valve surgery in a patient with factor VII deficiency.

Performing cardiac surgery on patients with bleeding diatheses poses significant challenges since these patients are at an increased risk for complications secondary to excessive bleeding. Despite its rarity, patients with factor VII (FVII) deficiency may require invasive procedures such as cardiac surgery. However, we lack guidelines on their pre-, peri-, and post-operative management. As FVII deficiency is rare, it seems unlikely to design and learn from large clinical studies. Instead, we need to base our clinical decision-making on single reported cases and registry data. Herein, we present the rare case of a patient with FVII deficiency who underwent double valve surgery. Pre-operatively, activated recombinant FVII (rFVIIa) was administered to reduce the risk of bleeding. Nevertheless, the patient experienced major bleeding. This case highlights the significance of FVII deficiency in patients undergoing cardiac surgery and emphasizes the importance of adequate and appropriate transfusion of blood products for these patients.

Radiodensity Analysis of Lateral Column Superconstruct Fixation Sites in Midfoot Charcot Neuroarthropathy.

Lateral column deterioration and subsequent loss of function poses a challenge for limb preservation in patients with Charcot neuroarthropathy (CN). Application of "superconstructs" provides stability and clinical improvement to an often-ulcerated lateral foot. This study examines radiodensity in Hounsfield units (HU) to compare bone quality of lateral column fixation targets using computed tomography (CT) scans between patients with and without midfoot CN. A retrospective chart review identified control (nondiabetic, non-CN; n = 29) and midfoot CN (n = 21) groups. Patient demographics and medical history were collected. Two reviewers measured the mean HU of circular regions of interest centered on the fourth and fifth metatarsal heads as well as the anterior, middle, and posterior thirds of the calcaneus. Radiodensity was compared between groups, among calcaneal locations, Eichenholtz stages and Brodsky types. A p value ≤.05 was considered statistically significant. Age and body mass index were not significantly different between groups. The CN group exhibited greater HU than the control group at the metatarsal head and calcaneus (p < .001). The anterior calcaneus exhibited greater HU than the posterior calcaneus in the CN group (p = .02). The difference in HU was not statistically significant between Stages 0-1 and Stages 2-3 or midfoot Brodsky Types. Indirect bone density analysis revealed an increased density in CN compared to control patients with no significant difference between midfoot CN stages or types. The anterior calcaneus was the densest rearfoot bone among the CN patients, a result that may have implications in surgical fixation.

Radiodensity Analysis of Medial Column Superconstruct Fixation Sites in Midfoot Charcot Neuroarthropathy.

Charcot neuroarthropathy (CN) is a highly destructive, pathologic process with devastating consequences to foot structure and viability. The use of intramedullary fixation "superconstructs" allows for "re-bar" support of compromised bone and allows for some dynamic fixation. This study examines radiodensity in Hounsfield units (HU) to compare bone quality of medial column fixation targets using computed tomography scans between patients with and without midfoot CN. A retrospective chart review identified control (nondiabetic, non-CN; n = 29) and midfoot CN (n = 21) groups. Patient demographics and medical history were collected. Two reviewers measured the mean HU of a circular region of interest centered on the first metatarsal head and the anterior, middle, and posterior thirds of the talar body. Radiodensity was compared between groups, and among talar locations, Eichenholtz stages and Brodsky types, with statistical significance set at p ≤ .05. Age and body mass index were not significantly different between groups. The CN group maintained greater mean HU than the control group at the metatarsal head (p < .001), and talar body locations (p < .019). The difference in mean HU of these bones was not statistically significant between Stages 0 to 1 and Stages 2 to 3 or Brodsky Types 1 and 2. Mean HU differences among talus positions were not statistically significant. Indirect bone density analysis using HU showed an increased density in CN patients with no significant difference among talar body locations or midfoot Charcot stages and types. These results may assist in optimizing fixation length. Future studies may examine these densities in ankle CN.

Heat shock protein 27 immune complex altered signaling and transport (ICAST): Novel mechanisms of attenuating inflammation.

Blood levels of heat shock protein (HSP27) and natural IgG auto-antibodies to HSP27 (AAbs) are higher in healthy controls compared to cardiovascular disease patients. Vaccination of mice with recombinant HSP25 (rHSP25, murine ortholog of human rHSP27) increased AAb levels, attenuated atherogenesis and reduced plaque inflammation and cholesterol content. We sought to determine if the HSP27 immune complex (IC) altered MΦ inflammation signaling (Toll Like Receptor 4; TLR4), and scavenger receptors involved in cholesterol uptake (SR-AI, CD-36). Combining a validated polyclonal IgG anti-HSP27 antibody (PAb) with rHSP27 enhanced binding to THP-1 MΦ cell membranes and activation of NF-κB signaling via TLR4, competing away LPS and effecting an anti-inflammatory cytokine profile. Similarly, adding the PAb with rHSP27 enhanced binding to SR-AI and CD-36, as well as lowered oxLDL binding in HEK293 cells separately transfected with SR-AI and CD-36, or THP-1 MΦ. Finally, the PAb enhanced the uptake and internalization of rHSP27 in THP-1 MΦ. Thus, the HSP27 IC potentiates HSP27 cell membrane signaling with receptors involved in modulating inflammation and cholesterol uptake, as well as HSP27 internalization. Going forward, we are focusing on the development of HSP27 Immune Complex Altered Signaling and Transport (ICAST) as a means of modulating inflammation.

D3R grand challenge 4: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies.

The Drug Design Data Resource (D3R) aims to identify best practice methods for computer aided drug design through blinded ligand pose prediction and affinity challenges. Herein, we report on the results of Grand Challenge 4 (GC4). GC4 focused on proteins beta secretase 1 and Cathepsin S, and was run in an analogous manner to prior challenges. In Stage 1, participant ability to predict the pose and affinity of BACE1 ligands were assessed. Following the completion of Stage 1, all BACE1 co-crystal structures were released, and Stage 2 tested affinity rankings with co-crystal structures. We provide an analysis of the results and discuss insights into determined best practice methods.

Intraosseous gout mimicking giant cell tumor of the patella.

Intraosseous gout involving the patella is an unusual presentation of the common inflammatory crystal deposition disease. In most reported cases of gout in the patella, there is prominent involvement of the adjacent patellar or quadriceps tendons of the extensor mechanism. A report from Japan describes another pattern of deposition, with a lesion arising in the synchondrosis of a bipartite patella. We present a case of a patient with no known history of gout experiencing vague anterior knee pain and subtle but rapidly progressive findings of a patellar lucent lesion on radiographs. No other cause for the patient's pain was identified on imaging. No prominent involvement of surrounding tendinous structures on MRI, unipartite patellar morphology, normal serum uric acid levels, rapid growth, and nonspecific appearance of the lesion led to a working diagnosis of patellar giant cell tumor. Biopsy of the lesion was performed to guide further management, which yielded the unexpected result of crystalline deposits consistent with gout.

D3R Grand Challenge 3: blind prediction of protein-ligand poses and affinity rankings.

The Drug Design Data Resource aims to test and advance the state of the art in protein-ligand modeling by holding community-wide blinded, prediction challenges. Here, we report on our third major round, Grand Challenge 3 (GC3). Held 2017-2018, GC3 centered on the protein Cathepsin S and the kinases VEGFR2, JAK2, p38-α, TIE2, and ABL1, and included both pose-prediction and affinity-ranking components. GC3 was structured much like the prior challenges GC2015 and GC2. First, Stage 1 tested pose prediction and affinity ranking methods; then all available crystal structures were released, and Stage 2 tested only affinity rankings, now in the context of the available structures. Unique to GC3 was the addition of a Stage 1b self-docking subchallenge, in which the protein coordinates from all of the cocrystal structures used in the cross-docking challenge were released, and participants were asked to predict the pose of CatS ligands using these newly released structures. We provide an overview of the outcomes and discuss insights into trends and best-practices.

Coronary artery disease in post-menopausal women: are there appropriate means of assessment?

The recognition of sex differences in cardiovascular disease, particularly the manifestations of coronary artery disease (CAD) in post-menopausal women, has introduced new challenges in not only understanding disease mechanisms but also identifying appropriate clinical means of assessing the efficacy of management strategies. For example, the majority of treatment algorithms for CAD are derived from the study of males, focus on epicardial stenoses, and inadequately account for the small intramyocardial vessel disease in women. However, newer investigational modalities, including stress perfusion cardiac magnetic resonance imaging and positron emission tomography are providing enhanced diagnostic accuracy and prognostication for women with microvascular disease. Moreover, these investigations may soon be complemented by simpler screening tools such as retinal vasculature imaging, as well as novel biomarkers (e.g. heat shock protein 27). Hence, it is vital that robust, sex-specific cardiovascular imaging modalities and biomarkers continue to be developed and are incorporated into practice guidelines that are used to manage women with CAD, as well as gauge the efficacy of any new treatment modalities. This review provides an overview of some of the sex differences in CAD and highlights emerging advances in the investigation of CAD in post-menopausal women.

Overview of the SAMPL6 host-guest binding affinity prediction challenge.

Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host-guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy.

D3R Grand Challenge 2: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies.

The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total. Procedurally, GC2 mimicked Grand Challenge 2015 (GC2015), with a Stage 1 subchallenge testing ligand pose prediction methods and ranking and scoring methods, and a Stage 2 subchallenge testing only ligand ranking and scoring methods after the release of all blinded co-crystal structures. Two smaller curated sets of 18 and 15 ligands were developed to test alchemical free energy methods. This overview summarizes all aspects of GC2, including the dataset details, challenge procedures, and participant results. We also consider implications for progress in the field, while highlighting methodological areas that merit continued development. Similar to GC2015, the outcome of GC2 underscores the pressing need for methods development in pose prediction, particularly for ligand scaffolds not currently represented in the Protein Data Bank ( http://www.pdb.org ), and in affinity ranking and scoring of bound ligands.

Overview of the SAMPL5 host-guest challenge: Are we doing better?

The ability to computationally predict protein-small molecule binding affinities with high accuracy would accelerate drug discovery and reduce its cost by eliminating rounds of trial-and-error synthesis and experimental evaluation of candidate ligands. As academic and industrial groups work toward this capability, there is an ongoing need for datasets that can be used to rigorously test new computational methods. Although protein-ligand data are clearly important for this purpose, their size and complexity make it difficult to obtain well-converged results and to troubleshoot computational methods. Host-guest systems offer a valuable alternative class of test cases, as they exemplify noncovalent molecular recognition but are far smaller and simpler. As a consequence, host-guest systems have been part of the prior two rounds of SAMPL prediction exercises, and they also figure in the present SAMPL5 round. In addition to being blinded, and thus avoiding biases that may arise in retrospective studies, the SAMPL challenges have the merit of focusing multiple researchers on a common set of molecular systems, so that methods may be compared and ideas exchanged. The present paper provides an overview of the host-guest component of SAMPL5, which centers on three different hosts, two octa-acids and a glycoluril-based molecular clip, and two different sets of guest molecules, in aqueous solution. A range of methods were applied, including electronic structure calculations with implicit solvent models; methods that combine empirical force fields with implicit solvent models; and explicit solvent free energy simulations. The most reliable methods tend to fall in the latter class, consistent with results in prior SAMPL rounds, but the level of accuracy is still below that sought for reliable computer-aided drug design. Advances in force field accuracy, modeling of protonation equilibria, electronic structure methods, and solvent models, hold promise for future improvements.

Blind prediction of cyclohexane-water distribution coefficients from the SAMPL5 challenge.

In the recent SAMPL5 challenge, participants submitted predictions for cyclohexane/water distribution coefficients for a set of 53 small molecules. Distribution coefficients (log D) replace the hydration free energies that were a central part of the past five SAMPL challenges. A wide variety of computational methods were represented by the 76 submissions from 18 participating groups. Here, we analyze submissions by a variety of error metrics and provide details for a number of reference calculations we performed. As in the SAMPL4 challenge, we assessed the ability of participants to evaluate not just their statistical uncertainty, but their model uncertainty-how well they can predict the magnitude of their model or force field error for specific predictions. Unfortunately, this remains an area where prediction and analysis need improvement. In SAMPL4 the top performing submissions achieved a root-mean-squared error (RMSE) around 1.5 kcal/mol. If we anticipate accuracy in log D predictions to be similar to the hydration free energy predictions in SAMPL4, the expected error here would be around 1.54 log units. Only a few submissions had an RMSE below 2.5 log units in their predicted log D values. However, distribution coefficients introduced complexities not present in past SAMPL challenges, including tautomer enumeration, that are likely to be important in predicting biomolecular properties of interest to drug discovery, therefore some decrease in accuracy would be expected. Overall, the SAMPL5 distribution coefficient challenge provided great insight into the importance of modeling a variety of physical effects. We believe these types of measurements will be a promising source of data for future blind challenges, especially in view of the relatively straightforward nature of the experiments and the level of insight provided.

D3R grand challenge 2015: Evaluation of protein-ligand pose and affinity predictions.

The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challenges for both target datasets were conducted in two stages, with the first stage testing pose predictions and the capacity to rank compounds by affinity with minimal structural data; and the second stage testing methods for ranking compounds with knowledge of at least a subset of the ligand-protein poses. An additional sub-challenge provided small groups of chemically similar HSP90 compounds amenable to alchemical calculations of relative binding free energy. Unlike previous blinded Challenges, we did not provide cognate receptors or receptors prepared with hydrogens and likewise did not require a specified crystal structure to be used for pose or affinity prediction in Stage 1. Given the freedom to select from over 200 crystal structures of HSP90 in the PDB, participants employed workflows that tested not only core docking and scoring technologies, but also methods for addressing water-mediated ligand-protein interactions, binding pocket flexibility, and the optimal selection of protein structures for use in docking calculations. Nearly 40 participating groups submitted over 350 prediction sets for Grand Challenge 2015. This overview describes the datasets and the organization of the challenge components, summarizes the results across all submitted predictions, and considers broad conclusions that may be drawn from this collaborative community endeavor.

From strategy to action: how top managers' support increases middle managers' commitment to innovation implementation in health care organizations.

BACKGROUND: Evidence suggests that top managers' support influences middle managers' commitment to innovation implementation. What remains unclear is how top managers' support influences middle managers' commitment. Results may be used to improve dismal rates of innovation implementation. METHODS: We used a mixed-method sequential design. We surveyed (n = 120) and interviewed (n = 16) middle managers implementing an innovation intended to reduce health disparities in 120 U.S. health centers to assess whether top managers' support directly influences middle managers' commitment; by allocating implementation policies and practices; or by moderating the influence of implementation policies and practices on middle managers' commitment. For quantitative analyses, multivariable regression assessed direct and moderated effects; a mediation model assessed mediating effects. We used template analysis to assess qualitative data. FINDINGS: We found support for each hypothesized relationship: Results suggest that top managers increase middle managers' commitment by directly conveying to middle managers that innovation implementation is an organizational priority (ß = 0.37, p = .09); allocating implementation policies and practices including performance reviews, human resources, training, and funding (bootstrapped estimate for performance reviews = 0.09; 95% confidence interval [0.03, 0.17]); and encouraging middle managers to leverage performance reviews and human resources to achieve innovation implementation. PRACTICE IMPLICATIONS: Top managers can demonstrate their support directly by conveying to middle managers that an initiative is an organizational priority, allocating implementation policies and practices such as human resources and funding to facilitate innovation implementation, and convincing middle managers that innovation implementation is possible using available implementation policies and practices. Middle managers may maximize the influence of top managers' support on their commitment by communicating with top managers about what kind of support would be most effective in increasing their commitment to innovation implementation.

Updates on the Applications of Spectral Computed Tomography for Musculoskeletal Imaging.

Spectral CT represents a novel imaging approach that can noninvasively visualize, quantify, and characterize many musculoskeletal pathologies. This modality has revolutionized the field of radiology by capturing CT attenuation data across multiple energy levels and offering superior tissue characterization while potentially minimizing radiation exposure compared to traditional enhanced CT scans. Despite MRI being the preferred imaging method for many musculoskeletal conditions, it is not viable for some patients. Moreover, this technique is time-consuming, costly, and has limited availability in many healthcare settings. Thus, spectral CT has a considerable role in improving the diagnosis, characterization, and treatment of gout, inflammatory arthropathies, degenerative disc disease, osteoporosis, occult fractures, malignancies, ligamentous injuries, and other bone-marrow pathologies. This comprehensive review will delve into the diverse capabilities of dual-energy CT, a subset of spectral CT, in addressing these musculoskeletal conditions and explore potential future avenues for its integration into clinical practice.

Pre-operative imaging with CA125 is a poor predictor for granulosa cell tumors.

OBJECTIVE: To determine the radiographic characteristics of ovarian granulosa cell tumors (GCTs) and to evaluate the use of CA125 levels >35 in combination with imaging as an algorithm for preoperative diagnosis. METHODS: A retrospective analysis of women from two academic medical centers who were diagnosed with ovarian GCT between January 1998 and August 2012 was conducted. Clinical data included tumor appearance on pre-operative imaging and CA125 levels. Ovarian cysts were defined as complex if imaging exhibited multicystic areas, hemorrhagic, solid, or cystic and solid components. A CA125 level >35 was abnormal. RESULTS: One hundred and fifteen women were diagnosed with GCTs, of whom 63 underwent pre-operative imaging. Median age at surgery was 46 years (12-87). Forty women had preoperative ultrasounds, 43 had CT scans and 20 underwent both modalities. GCTs were almost exclusively classified as complex cysts in 62 (98%) cases. The most common morphology was solid and cystic (n=44 (70%)). Forty-four (70%) patients had tumors >10 cm. Forty-two patients had a pre-operative CA125 performed. Eighteen (43%) patients had complex masses and CA125 >35. Twenty-three (55%) had CA125 <35 with a complex mass, and one (2%) had a unilocular cyst with a CA125 >35. CONCLUSIONS: In this study, there was a near equal distribution of patients with complex masses and CA125 levels > or <35. If established strategies to predict malignancy are applied to GCTs, we will frequently fail to make the diagnosis pre-operatively. Additional research is necessary to generate an appropriate algorithm to guide pre-operative referral to a gynecologic oncologist.

Chemoselective hydroamination of vinyl arenes catalyzed by an NHC-amidate-alkoxide Pd(II) complex and p-TsOH.

The hydroamination of various substituted vinyl arenes with benzenesulfonamide was explored using an NHC-amidate-alkoxide palladium catalyst in conjunction with p-TsOH. Utilizing halide-substituted and electron-rich vinyl arenes, this methodology selectively furnished the cross-coupled hydroamination products in moderate to excellent yields in a Markovnikov fashion while greatly reducing undesired acid-catalyzed homocoupling of the vinyl arenes. Electron-rich vinyl arenes typically required milder conditions than electron-poor ones. While most effective for para-substituted substrates, the catalyst system also furnished the desired products from ortho- and meta-substituted vinyl arenes with high chemoselectivities.

A New Perspective to Longstanding Challenges with Outpatient Hyperkalemia: A Narrative Review.

Purpose of Review: Outpatient hyperkalemia is a common problem with potentially deadly consequences. Potassium level thresholds to treat outpatient hyperkalemia are unstandardized and variable, leaving health care providers to rely on their own clinical judgment. This narrative review highlights the challenges of outpatient hyperkalemia management and includes recommendations for future studies that may standardize treatment, improve patient outcomes, and optimize health care utilization. Sources of Information: PubMed, Google Scholar, and the reference lists of identified articles were used to include English, peer-reviewed studies and guidelines for this review. Methods: This narrative review examines outpatient hyperkalemia from both a laboratory and clinical perspective. In addition to peer-reviewed literature, guidelines and expert consensus statements were included to highlight the inconsistencies and paucity of evidence that health care providers rely on to make clinical decisions. Key Findings: There are multiple reasons why outpatient hyperkalemia management is both challenging and sub-optimal. Clinicians must discern if the potassium level result is accurate and, if so, does the result warrant referral to the emergency department. Factitious hyperkalemia, or falsely elevated potassium level results due to analytical errors, occurs frequently, but there are no ways to identify it other than for hemolyzed samples. Additionally, guidelines and expert panels are inconsistent on the thresholds for treatment and the management of hyperkalemia. Finally, there are inconsistencies between laboratories as to when and how providers are notified of results, and the suggested thresholds for urgent management. A study that integrates the expertise of clinical biochemists and clinicians is needed to inform evidence-based guidelines for the management of outpatient hyperkalemia. Limitations: This was a comprehensive review of what is known and what still needs to be understood for the management of outpatient hyperkalemia. A formal tool to assess the quality of the included studies was not used and selection bias may have occurred.

Raison de la revue: L'hyperkaliémie ambulatoire est fréquente et peut avoir des conséquences mortelles. Les seuils de potassium justifiant le traitement de l'hyperkaliémie ambulatoire varient et ne sont pas normalisés; les professionnels de la santé doivent par conséquent s'en remettre à leur propre jugement clinique. Cette revue narrative met en évidence les défis liés à la prise en charge de l'hyperkaliémie ambulatoire et comprend des recommandations pour de futures études pour standardiser le traitement, améliorer les résultats des patients et optimiser l'utilisation des soins de santé. Sources d'information: PubMed, Google Scholar et les listes de références des articles répertoriés ont été utilisés pour inclure les études évaluées par les pairs et les lignes directrices rédigées en anglais. Méthodologie: Cette revue narrative examine la prise en charge de l'hyperkaliémie ambulatoire du point de vue clinique et paraclinique. En plus des articles évalués par les pairs, on a inclus des lignes directrices et des déclarations de consensus d'experts afin de mettre en évidence les incohérences et la rareté des données probantes sur lesquelles s'appuient les prestataires de soins de santé pour prendre des décisions cliniques. Principaux resultants: Plusieurs raisons peuvent expliquer pourquoi la prise en charge de l'hyperkaliémie ambulatoire est à la fois difficile et sous-optimale. Les cliniciens doivent juger eux-mêmes si le résultat du potassium est exact et, dans l'affirmative, déterminer s'il justifie l'aiguillage du patient vers les urgences. L'hyperkaliémie factice, soit des taux de potassium faussement élevés en raison d'erreurs analytiques, est fréquente, mais il n'existe aucun moyen de l'établir à l'exception des échantillons hémolysés. Aussi, les lignes directrices et les groupes d'experts ne s'entendent pas sur les seuils de traitement et de prise en charge de l'hyperkaliémie. Enfin, on observe des incohérences entre les laboratoires quant au moment et à la façon dont les prestataires sont informés des résultats, de même qu'en ce qui concerne les seuils suggérés pour une prise en charge urgente. Une étude intégrant l'expertise des biochimistes cliniques et des cliniciens est nécessaire pour éclairer des lignes directrices fondées sur des données probantes pour la prise en charge de l'hyperkaliémie ambulatoire. Limites: Il s'agit d'un examen complet de ce que l'on connaît et de ce qui doit encore être compris au sujet de la prise en charge de l'hyperkaliémie ambulatoire. Des biais de sélection pourraient s'être introduits puisqu'aucun outil formel n'a été utilisé pour évaluer les études incluses.