National Recommendations against Prostate Specific Antigen Screening versus Statewide Medicaid Expansion Initiatives: A Battle of the Titans.

PURPOSE: Medicaid expansion under the Patient Protection and Affordable Care Act occurred almost concurrently with 2012 U.S. Preventive Services Task Force recommendations against prostate specific antigen screening. Here the relative influence on prostate specific antigen screening rates by 2 concurrent and opposing system-level policy initiatives is investigated: improved access to care and change in clinical practice guidelines. MATERIALS AND METHODS: Behavioral Risk Factor Surveillance System data from years 2012 to 2018 were analyzed for trends in self-reported prostate specific antigen screening and insurance coverage. Subanalyses included state Medicaid expansion status and respondent federal poverty level. Multivariable logistic regression was performed to evaluate factors associated with prostate specific antigen screening. RESULTS: From 2012 to 2018 prostate specific antigen screening predominantly declined with a notable exception of an increase of 7.3% for men at <138% federal poverty level between 2011 and 2013 in early expansion states. Initial increases did not continue, and screening trends mirrored those of nonexpansion states by 2018. Notably, 2014 planned expansions states did not follow this trend with minimal change between 2015 and 2017 compared to declines in early expansion states and nonexpansion states (-0.4% vs -6.7% and -8.6%, respectively). CONCLUSIONS: Medicaid expansion was associated with increased rates of insured men at <138% federal poverty level from 2012 to 2018 in early expansion states. In this group, initial increases in prostate specific antigen screening were not durable and followed the trend of reduced screening seen across the United States. In planned expansions states the global drop in prostate specific antigen screening from 2016 to 2018 was offset in men at <138% federal poverty level by expanding access to care. Nonexpansion states showed a steady decline in prostate specific antigen screening rates. This suggests that policy such as U.S. Preventive Services Task Force recommendations against screening competes with and often outmatches access to care.

Human pluripotent stem cell-derived neural constructs for predicting neural toxicity.

Human pluripotent stem cell-based in vitro models that reflect human physiology have the potential to reduce the number of drug failures in clinical trials and offer a cost-effective approach for assessing chemical safety. Here, human embryonic stem (ES) cell-derived neural progenitor cells, endothelial cells, mesenchymal stem cells, and microglia/macrophage precursors were combined on chemically defined polyethylene glycol hydrogels and cultured in serum-free medium to model cellular interactions within the developing brain. The precursors self-assembled into 3D neural constructs with diverse neuronal and glial populations, interconnected vascular networks, and ramified microglia. Replicate constructs were reproducible by RNA sequencing (RNA-Seq) and expressed neurogenesis, vasculature development, and microglia genes. Linear support vector machines were used to construct a predictive model from RNA-Seq data for 240 neural constructs treated with 34 toxic and 26 nontoxic chemicals. The predictive model was evaluated using two standard hold-out testing methods: a nearly unbiased leave-one-out cross-validation for the 60 training compounds and an unbiased blinded trial using a single hold-out set of 10 additional chemicals. The linear support vector produced an estimate for future data of 0.91 in the cross-validation experiment and correctly classified 9 of 10 chemicals in the blinded trial.

Thromboprophylaxis With Heparin During Orthotopic Liver Transplantation: Comparison of Hepcon HMS Plus and Anti-Xa Assays for Low-Range Heparin.

OBJECTIVES: The purpose of this study was to compare the agreement between two heparin assays, Hepcon HMS plus/Kaolin-ACT and Anti-Xa, and their predictive power in detecting circulating heparin levels post-reperfusion of the liver graft when compared with thromboelastogram (TEG) r time ratio in patients undergoing orthotopic liver transplantation (OLT). DESIGN: Prospective, observational cohort study design. SETTING: Single center, university hospital. PARTICIPANTS: Thirty-eight consecutive adults who had undergone liver transplant. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Paired arterial blood samples were collected before surgical incision, 5 minutes after administration of an average dose of 2,054±771 units of intravenous unfractionated heparin before caval cross-clamping, 5 minutes after portal reperfusion, 5 minutes after hepatic artery reperfusion, and 1 hour after hepatic artery reperfusion. The observations that heparin assay measurements were within the predetermined limits of agreement, strongly suggested the two heparin assays (Hepcon HMS plus and Anti-Xa assay) are interchangeable during prophylactic heparin dose therapy during OLT. Post-reperfusion, receiver operating characteristic curve analysis revealed high accuracy in measuring circulating heparin levels with both Anti-Xa and Hepcon HMS assays when compared with the TEG r time ratio assay. CONCLUSIONS: The point-of-care Hepcon HMS plus/Kaolin-ACT (activated clotting time) assay appeared to be a reliable alternative to the more expensive and laboratory-required Anti-Xa assay in monitoring the response to intravenous heparin in patients undergoing OLT.

Epsilon-Aminocaproic Acid Has No Association With Thromboembolic Complications, Renal Failure, or Mortality After Liver Transplantation.

OBJECTIVES: To examine the role of epsilon-aminocaproic acid (EACA) administered after reperfusion of the donor liver in the incidences of thromboembolic events and acute kidney injury within 30 days after orthotopic liver transplantation. One-year survival rates between the EACA-treated and EACA-nontreated groups also were examined. DESIGN: Retrospective, observational, cohort study design. SETTING: Single-center, university hospital. PARTICIPANTS: The study included 708 adult liver transplantations performed from 2008 to 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: EACA administration was not associated with incidences of intracardiac thrombosis/pulmonary embolism (1.3%) or intraoperative death (0.6%). Logistic regression (n = 708) revealed 2 independent risk factors associated with myocardial ischemia (age and pre-transplant vasopressor use) and 8 risk factors associated with the need for post-transplant dialysis (age, female sex, redo orthotopic liver transplantation, preoperative sodium level, pre-transplant acute kidney injury or dialysis, platelet transfusion, and re-exploration within the first week after transplant); EACA was not identified as a risk factor for either outcome. One-year survival rates were similar between groups: 92% in EACA-treated group versus 93% in the EACA-nontreated group. CONCLUSIONS: The antifibrinolytic, EACA, was not associated with an increased incidence of thromboembolic complications or postoperative acute kidney injury, and it did not alter 1-year survival after liver transplantation.

Interactions of the Metalloregulatory Protein SloR from Streptococcus mutans with Its Metal Ion Effectors and DNA Binding Site.

UNLABELLED: Streptococcus mutans is the causative agent of dental caries, a significant concern for human health, and therefore an attractive target for therapeutics development. Previous work in our laboratory has identified a homodimeric, manganese-dependent repressor protein, SloR, as an important regulator of cariogenesis and has used site-directed mutagenesis to map functions to specific regions of the protein. Here we extend those studies to better understand the structural interaction between SloR and its operator and its effector metal ions. The results of DNase I assays indicate that SloR protects a 42-bp region of DNA that overlaps the sloABC promoter on the S. mutans UA159 chromosome, while electrophoretic mobility shift and solution binding assays indicate that each of two SloR dimers binds to this region. Real-time semiquantitative reverse transcriptase PCR (real-time semi-qRT-PCR) experiments were used to determine the individual base pairs that contribute to SloR-DNA binding specificity. Solution studies indicate that Mn(2+) is better than Zn(2+) at specifically activating SloR to bind DNA, and yet the 2.8-Å resolved crystal structure of SloR bound to Zn(2+) provides insight into the means by which selective activation by Mn(2+) may be achieved and into how SloR may form specific interactions with its operator. Taken together, these experimental observations are significant because they can inform rational drug design aimed at alleviating and/or preventing S. mutans-induced caries formation. IMPORTANCE: This report focuses on investigating the SloR protein as a regulator of essential metal ion transport and virulence gene expression in the oral pathogen Streptococcus mutans and on revealing the details of SloR binding to its metal ion effectors and binding to DNA that together facilitate this expression. We used molecular and biochemical approaches to characterize the interaction of SloR with Mn(2+) and with its SloR recognition element to gain a clearer picture of the regulatory networks that optimize SloR-mediated metal ion homeostasis and virulence gene expression in S. mutans. These experiments can have a significant impact on caries treatment and/or prevention by revealing the S. mutans SloR-DNA binding interface as an appropriate target for the development of novel therapeutic interventions.

Sugar-Based Polyamides: Self-Organization in Strong Polar Organic Solvents.

Periodic patterns resembling spirals were observed to form spontaneously upon unassisted cooling of d-glucaric acid- and d-galactaric acid-based polyamide solutions in N-methyl-N-morpholine oxide (NMMO) monohydrate. Similar observations were made in d-galactaric acid-based polyamide/ionic liquid (IL) solutions. The morphologies were investigated by optical, polarized light and confocal microscopy assays to reveal pattern details. Differential scanning calorimetry was used to monitor solution thermal behavior. Small- and wide-angle X-ray scattering data reflected the complex and heterogeneous nature of the self-organized patterns. Factors such as concentration and temperature were found to influence spiral dimensions and geometry. The distance between rings followed a first-order exponential decay as a function of polymer concentration. Fourier-Transform Infrared Microspectroscopy analysis of spirals pointed to H-bonding between the solvent and the pendant hydroxyl groups of the glucose units from the polymer backbone. Tests on self-organization into spirals of ketal-protected d-galactaric acid polyamides in NMMO monohydrate confirmed the importance of the monosaccharide's pendant free hydroxyl groups on the formation of these patterns. Rheology performed on d-galactaric-based polyamides at high concentration in NMMO monohydrate solution revealed the optimum conditions necessary to process these materials as fibers by spinning. The self-organization of these sugar-based polyamides mimics certain biological materials.

Robotic approach to Giant multiloculated cystadenoma of the prostate: Initial experience.

Giant multiloculated cystadenoma of the prostate (GMPC) is a rare, massive and benign tumor. Recurrence rates after resection are low but have been recorded. An open approach is most common, with few laparoscopic and no robotic cases reported. We report on a case of a 65-year-old man with a new presentation of a 400 cc cystic prostatic mass thought to be GMPC. This patient underwent what is, to our knowledge, the first reported case of RARP in the treatment of GMPC. A robotic approach to massive GMPC was safe and efficacious in our initial experience.

A protocol for rapid pericyte differentiation of human induced pluripotent stem cells.

Pericytes play a critical role in promoting, regulating, and maintaining numerous vascular functions. Their dysfunction is a major contributor to the progression of vascular and neurodegenerative diseases, making them an ideal candidate for large-scale production for disease modeling and regenerative cell therapy. This protocol describes the rapid and robust differentiation of pericytes from human induced pluripotent stem cells (hiPSCs) while simultaneously generating a population of hiPSC-derived endothelial progenitor cells. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2017).

Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects.

Perhexiline has been used to treat hypertrophic cardiomyopathy. In addition to its effect on carnitine-palmitoyltransferase-1, it has mixed ion channel effects through inhibition of several cardiac ion currents. Effects on cardiac ion channels expressed in mammalian cells were assayed using a manual patch-clamp technique, action potential duration (APD) was measured in ventricular trabeculae of human donor hearts, and electrocardiogram effects were evaluated in healthy subjects in a thorough QT (TQT) study. Perhexiline blocked several cardiac ion currents at concentrations within the therapeutic range (150-600 ng/mL) with IC50 for hCav1.2 ∼ hERG < late hNav1.5. A significant APD shortening was observed in perhexiline-treated cardiomyocytes. The TQT study was conducted with a pilot part in 9 subjects to evaluate a dosing schedule that would achieve therapeutic and supratherapeutic perhexiline plasma concentrations on days 4 and 6, respectively. Guided by the results from the pilot, 104 subjects were enrolled in a parallel-designed part with a nested crossover comparison for the positive control. Perhexiline caused QTc prolongation, with the largest effect on ΔΔQTcF, 14.7 milliseconds at therapeutic concentrations and 25.6 milliseconds at supratherapeutic concentrations and a positive and statistically significant slope of the concentration-ΔΔQTcF relationship (0.018 milliseconds per ng/mL; 90%CI, 0.0119-0.0237 milliseconds per ng/mL). In contrast, the JTpeak interval was shortened with a negative concentration-JTpeak relationship, a pattern consistent with multichannel block. Further studies are needed to evaluate whether this results in a low proarrhythmic risk.

Meditative and mind-body practice among patients with genitourinary malignancy.

INTRODUCTION AND OBJECTIVE: Research on the utility of meditative and mind-body (MB) practices has increased dramatically in the last two decades and both have been suggested as useful adjuncts in coping with stressors associated with cancer survivorship. There exists little data on use among genitourinary (GU) cancer survivors. This study seeks to describe meditative and MB utilization among GU cancer survivors. METHODS: Analysis of data from the 2012 and 2017 National Health Interview Survey was conducted. Patients aged 40 and older reporting a history of any cancer diagnosis (including 3 GU cancers) were included in the analysis. We explored questions about meditative and MB practices in the past 12 months. Complex Samples Logistic regression was performed to compare the relationship between cancer status and use of these practices. RESULTS: Self-reported meditative practices were more prevalent in 2017 (17%) than in 2012 (5%). Patients who self-reported a cancer diagnosis of any kind were significantly more likely to utilize meditative practices. Patients with kidney cancer were significantly more likely to meditate and trended towards higher MB utilization. In contrast, bladder cancer patients were less likely to meditate and use MB practices. Increases in meditation were greater than those seen for MB in all groups. CONCLUSIONS: Meditative and MB practices increased in prevalence between 2012 and 2017 with notable heterogeneity between cancer types. Given the potential benefit, more broad incorporation into survivorship programs may be warranted. Future work should explore the significance of this heterogeneity and the utility of these practices to patients with urologic malignancy.

Pathologic nodal downstaging in men with clinically involved lymph nodes undergoing radical prostatectomy: Implications for definitive locoregional therapy.

A prostate cancer (CaP) patient with nonmetastatic but clinical positive lymph nodes (cN+) represents a difficult clinical scenario. We compare overall survival (OS) between cN+ men that underwent radical prostatectomy (RP) and were found to have negative node status (pN) with those found to have positive nodal status (pN+), and assess predictors of discordant nodal status. We queried the National Cancer Data Base between 2004 and 2015 for patients that were cT1-3 cN+ cM0 CaP treated with RP. Patients with 0 nodes, cT4, or cM1 disease were excluded. We compared groups based on pathologic nodal status: Discordant (cN+ -> pN) & Concordant (cN+ -> pN+). Kaplan Meier estimations were used to compare OS. Logistic regression was used to determine possible predictors of nodal status. We find that of 6470 cN+ patients, 1,367 (21.1%) underwent RP, 866 (13.4%) had confirmed nodal status. Discordant status was found in 159 (18.4%) and concordant staging in 707 (81.6%). Differences exist in PSA at diagnosis (7.3 vs. 11.2), biopsy group, # of nodes examined (7 vs. 10), race, and Charlson index. Discordant staging had longer OS compared to Concordant staging (P = 0.007) and similar OS to a 3:1 matched cohort of high risk localized CaP patients used as reference (P = 0.46). Lower Gleason Score (GG1-3) was associated with an increased likelihood of discordant staging. Clinical nodal staging is associated with a substantial false positive rate. Discordant status had better OS than Concordant status and similar OS to matched patients with localized CaP. Clinical nodal staging may inappropriately lead to noncurative therapy in a substantial number of men with potentially curable disease.

Nurse-led asthma services for children and young people: a survey of GPs' views.

AIM: To explore GPs' attitudes to nurse-led initiatives in the care of children with asthma. METHODS: A questionnaire was posted to 541 GPs in the study area, of whom 236 (43.6 per cent) responded. The data were analysed quantitatively. RESULTS: Of the 236 responders, 90 per cent did provide nurse-led services, 89 per cent believed that patients benefited from these, 84 per cent would consider referral to a nurse-led asthma clinic at the regional children's hospital and 79 per cent would refer to a satellite paediatric nurse-led clinic. CONCLUSION: GPs believe children's nurse-led asthma services benefit the GP's surgery, the regional children's hospital and the primary care trust. Improvements in communication between primary and secondary care are needed.

Endourologic Management of Stent Retained Over 22 Years in Patient with Duplicated Collecting System.

Background: Retained and subsequently encrusted stents can lead to a number of complications, the most dire being deterioration of renal function. Limited literature exists concerning endourologic management of stents retained for extreme durations and few that concerns patients with abnormal renal anatomy. Case Presentation: A 70-year-old man with history of Crohn's disease and partially duplicated collecting system presented with rising creatinine and was found to have bilateral retained Double-J stents, originally placed before small bowel resection 22 years prior. The patient underwent staged bilateral percutaneous nephrolithotomy with ultimate effective removal of both stents. The patient has had subsequent improvement in renal function and has not required dialysis. Conclusion: Removal of ureteral stents in a timely manner is paramount to prevent long-term retention and complication, but when required retained stents can be safely managed with a well-planned endourologic approach, even if significant deterioration in renal function has occurred.

Posterior Reversible Encephalopathy Syndrome Following Failure of Conservative Management in Renal Trauma: Case Report.

Blunt renal trauma is relatively common in children. Conservative management has become the mainstay of treatment. A 4-year-old boy presented following a fall onto his right abdomen resulting in renal trauma. Initial conservative management was followed by complete embolization of the kidney. The resulting continued hypertension, as well as endothelial disruption, resulted in PRES as manifested by a single instance of generalized seizure. The patient regained normal neurological function following nephrectomy. Better understanding of the potential for acute hypertensive crisis resulting in PRES in the urology community may result in more urgent and effective management in these scenarios.

Engineered Perineural Vascular Plexus for Modeling Developmental Toxicity.

There is a vital need to develop in vitro models of the developing human brain to recapitulate the biological effects that toxic compounds have on the brain. To model perineural vascular plexus (PNVP) in vitro, which is a key stage in embryonic development, human embryonic stem cells (hESC)-derived endothelial cells (ECs), neural progenitor cells, and microglia (MG) with primary pericytes (PCs) in synthetic hydrogels in a custom-designed microfluidics device are cocultured. The formation of a vascular plexus that includes networks of ECs (CD31+, VE-cadherin+), MG (IBA1+), and PCs (PDGFRß+), and an overlying neuronal layer that includes differentiated neuronal cells (ßIII Tubulin+, GFAP+) and radial glia (Nestin+, Notch2NL+), are characterized. Increased brain-derived neurotrophic factor secretion and differential metabolite secretion by the vascular plexus and the neuronal cells over time are consistent with PNVP functionality. Multiple concentrations of developmental toxicants (teratogens, microglial disruptor, and vascular network disruptors) significantly reduce the migration of ECs and MG toward the neuronal layer, inhibit formation of the vascular network, and decrease vascular endothelial growth factor A (VEGFA) secretion. By quantifying 3D cell migration, metabolic activity, vascular network disruption, and cytotoxicity, the PNVP model may be a useful tool to make physiologically relevant predictions of developmental toxicity.

Neurovascular Organotypic Culture Models Using Induced Pluripotent Stem Cells to Assess Adverse Chemical Exposure Outcomes.

Introduction: Human-induced pluripotent stem cells (iPSCs) represent a promising cell source for the construction of organotypic culture models for chemical toxicity screening and characterization. Materials and Methods: To characterize the effects of chemical exposure on the human neurovasculature, we constructed neurovascular unit (NVU) models consisting of endothelial cells (ECs) and astrocytes (ACs) derived from human-iPSCs, as well as human brain-derived pericytes (PCs). The cells were cocultured on synthetic poly(ethylene glycol) (PEG) hydrogels that guided the self-assembly of capillary-like vascular networks. High-content epifluorescence microscopy evaluated dose-dependent changes to multiple aspects of NVU morphology. Results: Cultured vascular networks underwent quantifiable morphological changes when incubated with vascular disrupting chemicals. The activity of predicted vascular disrupting chemicals from a panel of 38 compounds (U.S. Environmental Protection Agency) was ranked based on morphological features detected in the NVU model. In addition, unique morphological neurovascular disruption signatures were detected per chemical. A comparison of PEG-based NVU and Matrigel™-based NVU models found greater sensitivity and consistency in chemical detection by the PEG-based NVU models. Discussion: We suspect that specific morphological changes may be used for discerning adverse outcome pathways initiated by chemical exposure and rapid mechanistic characterization of chemical exposure to neurovascular function. Conclusion: The use of human stem cell-derived vascular tissue and PEG hydrogels in the construction of NVU models leads to rapid detection of adverse chemical effects on neurovascular stability. The use of multiple cell types in coculture elucidates potential mechanisms of action by chemicals applied to the model.

Computed Tomography with Intravenous Contrast Is Not Associated with Development of Acute Kidney Injury in Severely Injured Pediatric Patients.

Data for the incidence of acute kidney injury (AKI) related to intravenous contrast administration in the pediatric trauma population are limited. Obtaining a creatinine value before elective CT scans is a relatively accepted standard of care. We sought to determine whether there was any significant difference in the incidence of AKI between severely injured patients who received IV contrast and those who did not. We reviewed data from the trauma registry at our Level I pediatric trauma center. We limited the patients to severely injured pediatric traumas (<15 years old) directly transported from the scene of injury with a creatinine level measured on arrival. Two hundred and eleven patients were included in the study. AKI was defined by the criteria of the AKI Network. We then compared incidence of AKI in those who received a CT scan with IV contrast with those who did not receive IV contrast. The two groups were comparable in age, gender, Glasgow Coma Scale, Injury Severity Score, mean creatinine on arrival, and mean creatinine post-CT scan/arrival. There was no significant difference in AKI between the two. In a subgroup analysis of patients presenting in shock, there was no significant difference in AKI. Our study suggests that IV contrast is not associated with the development of AKI in severely injured pediatric trauma patients. Although obtaining a creatinine value before exposure is ideal, a CT scan with IV contrast in severely injured children should not be delayed to obtain a creatinine value.

Evaluation of PEG-based hydrogel influence on estrogen receptor driven responses in MCF7 breast cancer cells.

Extracellular matrix (ECM) mimicking hydrogel scaffolds have greatly improved the physiological relevance of in vitro assays, but introduce another dimension that creates variability in cell related readouts when compared to traditional 2D cells-on-plastic assays. We have developed a synthetic poly(ethylene glycol) (PEG) based ECM mimicking hydrogel and tested it against two gold standard animal-based naturally derived hydrogel scaffolds in MCF7 cell response. We have used the percent coefficient of variation (CV) as a metric to evaluate the reproducibility of said responses. Results indicated that PEG hydrogels performed similarly to naturally derived gold standards, and variance was similar in basic characterization assays, such as viability and cell adherence. PEG based hydrogels had lower CV values in estrogen receptor driven responses to several doses of estrogen in both estrogen receptor transactivation and estrogen induced proliferation.