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Marine heatwaves (MHWs) are increasing in frequency and intensity globally and are among the greatest threats to marine ecosystems. However, limited studies have characterized subsurface MHWs, particularly in shallow waters. We utilized nearly two decades of full water-column (~ 10 m) observations from a unique automated profiler in central California to characterize, for the first time, the vertical structure of MHWs in a shallow nearshore upwelling system. We found MHWs have similar average durations and intensities across all depths, but there were ~ 17% more bottom MHW days than surface MHW days. Nearly one third of bottom MHWs occurred independently of surface MHWs, indicating that satellites miss a significant fraction of events. MHWs showed distinct seasonality with more frequent and intense events during the fall/winter when weak stratification allowed for MHWs to occupy a larger portion of the water column and persist longer. During summer, strong stratification limited the vertical extent of MHWs, leading to surface- and bottom-trapped events with shorter durations and intensities. Additionally, MHW initiation and termination across depths was consistently linked to anomalously low and high coastal upwelling, respectively. This study highlights the need for expansion of subsurface monitoring of MHWs globally amid a warming planet., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The density of quasiparticles typically observed in superconducting qubits exceeds the value expected in equilibrium by many orders of magnitude. Can this out-of-equilibrium quasiparticle density still possess an energy distribution in equilibrium with the phonon bath? Here, we answer this question affirmatively by measuring the thermal activation of charge-parity switching in a transmon qubit with a difference in superconducting gap on the two sides of the Josephson junction. We then demonstrate how the gap asymmetry of the device can be exploited to manipulate its parity.

Background: Optimal rehabilitation programs for orthopedic joint replacement patients ensure faster return to function, earlier discharge from hospital, and improved patient satisfaction. Digital health interventions show promise as a supporting tool for re-enablement., Objective: The main goal of this mixed methods study was to examine the usability of the AIMS platform from the perspectives of both patients and clinicians. The aim of this study was to evaluate a re-enablement platform that we have developed that uses a holistic systems approach to address the de-enablement that occurs in hospitalized inpatients, with the older adult population most at risk. The Active and Independent Management System (AIMS) platform is anticipated to deliver improved patient participation in recovery and self-management through education and the ability to track rehabilitation progression in hospital and after patient discharge., Methods: Two well-known instruments were used to measure usability: the System Usability Scale (SUS) with 10 items and, for finer granularity, the User Experience Questionnaire (UEQ) with 26 items. In all, 26 physiotherapists and health care professionals evaluated the AIMS clinical portal; and 44 patients in hospital for total knee replacement, total hip replacement, or dynamic hip screw implant evaluated the AIMS app., Results: For the AIMS clinical portal, the mean SUS score obtained was 82.88 (SD 13.07, median 86.25), which would be considered good/excellent according to a validated adjective rating scale. For the UEQ, the means of the normalized scores (range -3 to +3) were as follows: attractiveness=2.683 (SD 0.100), perspicuity=2.775 (SD 0.150), efficiency=2.775 (SD 0.130), dependability=2.300 (SD 0.080), stimulation=1.950 (SD 0.120), and novelty=1.625 (SD 0.090). All dimensions were thus classed as excellent against the benchmarks, confirming the results from the SUS questionnaire. For the AIMS app, the mean SUS score obtained was 74.41 (SD 10.26), with a median of 77.50, which would be considered good according to the aforementioned adjective rating scale. For the UEQ, the means of the normalized scores were as follows: attractiveness=2.733 (SD 0.070), perspicuity=2.900 (SD 0.060), efficiency=2.800 (SD 0.090), dependability=2.425 (SD 0.060), stimulation=2.200 (SD 0.010), and novelty=1.450 (0.260). All dimensions were thus classed as excellent against the benchmarks (with the exception of novelty, which was classed as good), providing slightly better results than the SUS questionnaire., Conclusions: The study has shown that both the AIMS clinical portal and the AIMS app have good to excellent usability scores, and the platform provides a solid foundation for the next phase of research, which will involve evaluating the effectiveness of the platform in improving patient outcomes after total knee replacement, total hip replacement, or dynamic hip screw., (©Petros Papadopoulos, Mario Soflano, Thomas Connolly. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 14.05.2024.)

The dispersive interaction between a qubit and a cavity is ubiquitous in circuit and cavity quantum electrodynamics. It describes the frequency shift of one quantum mode in response to excitations in the other and, in closed systems, is necessarily bidirectional, i.e., reciprocal. Here, we present an experimental study of a nonreciprocal dispersive-type interaction between a transmon qubit and a superconducting cavity, arising from a common coupling to dissipative intermediary modes with broken time reversal symmetry. We characterize the qubit-cavity dynamics, including asymmetric frequency pulls and photon shot noise dephasing, under varying degrees of nonreciprocity by tuning the magnetic field bias of a ferrite component in situ. We introduce a general master equation model for nonreciprocal interactions in the dispersive regime, providing a compact description of the observed qubit-cavity dynamics agnostic to the intermediary system. Our result provides an example of quantum nonreciprocal phenomena beyond the typical paradigms of non-Hermitian Hamiltonians and cascaded systems.

Background: Cancer treatment is a key component of health care systems, and the increasing number of cancer medicines is expanding the treatment landscape. However, evidence of the impact on patients has been focused more on chemotherapy toxicity and symptom control and less on the effect of cancer medicines more broadly on patients' lives. Evolving electronic patient-reported outcome measures (ePROMs) presents the opportunity to secure early engagement of patients and clinicians in shaping the collection of quality-of-life metrics and presenting these data to better support the patient-clinician decision-making process., Objective: The aim of this study was to obtain initial feedback from patients and clinicians on the wireframes of a digital solution (patient app and clinician dashboard) for the collection and use of cancer medicines ePROMs., Methods: We adopted a 2-stage, mixed methods approach. Stage 1 (March to June 2019) consisted of interviews and focus groups with cancer clinicians and patients with cancer to explore the face validity of the wireframes, informed by the technology acceptance model constructs (perceived ease of use, perceived usefulness, and behavioral intention to use). In stage 2 (October 2019 to February 2020), the revised wireframes were assessed through web-based, adapted technology acceptance model questionnaires. Qualitative data (stage 1) underwent a framework analysis, and descriptive statistics were performed on quantitative data (stage 2). Clinicians and patients with cancer were recruited from NHS Greater Glasgow & Clyde, the largest health board in Scotland., Results: A total of 14 clinicians and 19 patients participated in a combination of stage 1 interviews and focus groups. Clinicians and patients indicated that the wireframes of a patient app and clinician dashboard for the collection of cancer medicines ePROMs would be easy to use and could focus discussions, and they would be receptive to using such tools in the future. In stage 1, clinicians raised the potential impact on workload, and both groups identified the need for adequate IT skills to use each technology. Changes to the wireframes were made, and in stage 2, clinicians (n=8) and patients (n=16) indicated it was "quite likely" that the technologies would be easy to use and they would be "quite likely" to use them in the future. Notably, clinicians indicated that they would use the dashboard to enable treatment decisions "with around half" of their patients., Conclusions: This study emphasizes the importance of consulting both patients and clinicians in the design of digital solutions. The wireframes were perceived positively by patients and clinicians who were willing to use such technologies if available in the future as part of routine care. However, challenges were raised, and some differences were identified between participant groups, which warrant further research., (©Emma Dunlop, Aimee Ferguson, Tanja Mueller, Kelly Baillie, Jennifer Laskey, Julie Clarke, Amanj Kurdi, Ann Wales, Thomas Connolly, Marion Bennie. Originally published in JMIR Formative Research (https://formative.jmir.org), 21.12.2023.)

Background: Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking., Methods: The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold considered P <5×10 - 8 ., Results: Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in FGD5 were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38; P =2.42×10 -6 ; African ancestry: HR, 1.51; P =4.43×10 - 3 ; HR in meta-analysis, 1.41; P =4.25×10 -8 ). FGD5 encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; meta P <0.01). Sensitivity analysis proved FGD5 common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment ( P >0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39; P =1.59×10 -5 )., Conclusions: In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms in FGD5 were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether FGD5 could be a therapeutic target., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT00475852., Competing Interests: Disclosures Dr Lanfear is a consultant for Amgen, Janssen, Ortho Diagnostics, and Duke Clinical Research Institute (Novartis) and has participated in clinical trials from Amgen, Bayer, and Janssen. Dr Francke is currently a consultant for Janssen and was previously employed by Janssen. Dr Connolly was previously employed by Janssen. Dr McNaughton has participated in clinical studies for Pfizer. Dr Tang is a consultant to Sequana Medical AG. The other authors report no conflicts.

Studies of the proteome would benefit greatly from methods to directly sequence and digitally quantify proteins and detect posttranslational modifications with single-molecule sensitivity. Here, we demonstrate single-molecule protein sequencing using a dynamic approach in which single peptides are probed in real time by a mixture of dye-labeled N-terminal amino acid recognizers and simultaneously cleaved by aminopeptidases. We annotate amino acids and identify the peptide sequence by measuring fluorescence intensity, lifetime, and binding kinetics on an integrated semiconductor chip. Our results demonstrate the kinetic principles that allow recognizers to identify multiple amino acids in an information-rich manner that enables discrimination of single amino acid substitutions and posttranslational modifications. With further development, we anticipate that this approach will offer a sensitive, scalable, and accessible platform for single-molecule proteomic studies and applications.

Objective: To analyse the outcomes of retroperitoneoscopic upper and lower moiety hemi-nephroureterectomy (HNU) and to assess the different variables that may have an impact on outcome; remnant moiety damage, morbidity and the need for secondary surgery., Methods: Prospectively recorded data of retroperitoneoscopic HNU's performed by a single surgeon from 2005 to 2018 were analysed. Patients were split into 2 groups according to moiety affected (UMHNU and LMHNU). Clinical presentation, underlying pathology, remnant moiety DRF on renal scintigraphy, and need for further surgery were recorded. Detailed operation notes were studied regards to renal vasculature, degree of dilatation, inflammatory changes and operative difficulties encountered. Renal loss was defined as remnant moiety DRF <10% post-operatively. Change in DRF was assessed regards to the moiety, pathology and age at surgery (<1 year, 1-2 years and ≥2 years). UMHNU group was further sub-divided into 3 subgroups: ureteroceles, ectopic ureters and 'other' pathology. Statistical analysis was performed using Fishers Exact test; findings were considered statistically significant at p < 0.05., Results: 78 operations met the inclusion criteria on 75 patients (3 bilateral). There were no conversions to open, and 67% were performed as day-case procedures (53/78 patients). In 91.2% (71/78) patients the procedure was definitive in resolving pathology and symptoms. 7 patients needed further procedures after HNU, 5 for ureterocele/ureteric stump. Overall, there was remnant moiety renal loss in 5.1% (4/78) patients, all with UM surgery (3 ectopic ureters and 1 ureterocele). All 4 operations were recorded prospectively as 'difficult operations' due to grossly dilated UM ureter/pelvis measuring >2 cm in diameter. 2 patients had a thinned out lower moiety (LM) sitting on top of the UM renal pelvis like a pancake with all vessels stretched over this dilated pelvis/ureter causing difficulty in accurate identification. There was intra-operative concern about some damage to LM vessels in 3 patients. Age <1year was also related to increased renal loss (2/8 patients <1 year, 1/25 patients 1-2 years, 1/45 patients ≥2 years of age P = 0.005)., Conclusion: Retroperitoneoscopic LMHNU is a safe and definitive procedure with rapid recovery and minimal scarring. UMHNU has higher rates of remnant moiety loss due to more complex renal pathology, but remains a safe, successful operation on the majority of patients. Renal damage was also related to age <1year (p = 0.005) and re-operation risk after UMHNU correlated to the presence of ureterocele (p = 0.003)., (Copyright © 2021 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

When and how people first settled in the Americas is an ongoing area of research and debate. The earliest sites typically only contain lithic artifacts that cannot be directly dated. The lack of human skeletal remains in these early contexts means that alternative sources of evidence are needed. Coprolites, and the DNA contained within them, are one such source, but unresolved issues concerning ancient DNA taphonomy and potential for contamination make this approach problematic. Here, we use fecal lipid biomarkers to demonstrate unequivocally that three coprolites dated to pre-Clovis are human, raise questions over the reliance on DNA methods, and present a new radiocarbon date on basketry further supporting pre-Clovis human occupation., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Aims: JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis., Methods and Results: Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 μg/mL), bivalirudin (6 μg/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively.JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P < 0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P < 0.001) and platelet-monocyte aggregates (P = 0.002). Compared to placebo, JNJ-9375 (250 μg/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P < 0.001) at low shear and 32.3% (4.9 to 51.8%; P = 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P < 0.001 for both) but not platelet-rich thrombus (P = ns for both)., Conclusion: Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. JNJ-9375 represents a novel class of anticoagulant with potential therapeutic applications., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)

7α-hydroxy-4-cholesten-3-one (C4) is an oxidative enzymatic product of cholesterol metabolism via cholesterol 7α-hydroxylase, an enzyme also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1). C4 is a stable intermediate in the rate limiting pathway of bile acid biosynthesis. Previous studies showed that plasma C4 levels correlated with CYP7A1 enzymatic activity and could serve as a biomarker for bile acid synthesis. Here we developed and qualified a simple and robust high-throughput method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to quantify C4 in rat and monkey plasma. As C4 being an endogenous compound, this method used calibration standards in 50/50: acetonitrile/water (v/v). In order to mimic the incurred samples, quality control samples were prepared in the authentic plasma. Stable isotope labeled C4 (C4-d 7 ) was used as the internal standard. The sample volume for analysis was 20μL and the sample preparation method was protein precipitation with acetonitrile. The average endogenous C4 concentrations, from 10 different lots of rat and monkey plasma, were 53.0±16.5ng/mL and 6.8±5.6ng/mL, respectively. Based on these observed endogenous C4 levels, the calibration curve ranges were established at 1-200ng/mL and 0.5-100ng/mL for rat assay and monkey assay, respectively. The method was qualified with acceptable accuracy, precision, linearity, and specificity. Matrix effect, recovery, and plasma stability of bench-top, freeze-thaw, and long-term frozen storage were also evaluated. The method has been successfully applied to pre-clinical studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Cryptococcus gattii (Cg) infection emerged in British Columbia in 1999. A longitudinal, clinical description of patients has not been reported., Methods: Medical records were reviewed for Cg patients identified through surveillance (1999-2007). Risk factors for Cg mortality were explored using multivariate Cox regression; longitudinal patterns in serum cryptococcal antigen (SCrAg) titers and the probability of chest cryptococcomas over time were estimated using cubic B-splines in mixed-effects regression models., Results: Among 152 patients, 111 (73.0%) were culture confirmed. Isolated lung infection was present in 105 (69.1%) patients; 47 (30.9%) had central nervous system infection, with or without lung involvement. Malignancy was the provisional diagnosis in 64 (42.1%) patients. Underlying diseases were present in 91 (59.9%) patients; 23 (15.1%) were immunocompromised, and 23 (15.1%) had asymptomatic disease. There were only 2 (1.8%) culture positive relapses, both within 12 months of follow-up. The estimated median time to resolution of lung cryptococcomas and decline in SCrAg titer to <1:8 was 2.8 and 2.9 years, respectively. Cg-related and all-cause mortality among culture-confirmed cases at 12 months' follow-up was 23.3% and 27.2%, respectively. Cg-related mortality was associated with age >50 years (hazard ratio [HR], 15.6; 95% confidence interval [CI], 1.9-130.5) and immunocompromise (HR, 5.8; CI, 1.5-21.6). All Cg-related mortality occurred among culture-positive cases within 1 year of diagnosis., Conclusions: Cryptococcomas and serum antigenemia were slow to resolve. However, late onset of failed therapy or relapse was uncommon, suggesting that delayed resolution of these findings does not require prolongation of treatment beyond that recommended by guidelines., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P-selectin on activated platelets induces formation of platelet-monocyte aggregates and promotes vascular inflammation and thrombosis. P-selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P-selectin antagonist PSI-697 on platelet-monocyte aggregate formation in humans., Methods and Results: In a double-blind, randomized, placebo-controlled crossover study, healthy smokers were randomized to receive either oral PSI-697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI-697 and placebo. Platelet-monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor-activating peptide (TRAP; 0.1 to 1.0 μm/L). The ex vivo addition of TRAP caused a concentration-dependent increase in platelet-monocyte aggregates from 8.2% to 94.8% (P<0.001). At 4 and 24 hours, plasma concentrations of PSI-697 increased to 1906 and 83 ng/mL, respectively (P<0.001). PSI-697 had no demonstrable effect on either stimulated or unstimulated platelet-monocyte aggregates at 4 or 24 hours (P>0.05). P-selectin-blocking antibody (CLB-Thromb6), but not PSI-697, inhibited both stimulated and unstimulated platelet-monocyte aggregate formation in vitro (P<0.001)., Conclusions: The novel small-molecule P-selectin antagonist PSI-697 did not inhibit basal or stimulated platelet-monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established., Clinical Trial Registration: URL: http://EudraCT.ema.europa.eu Unique identifier: 2007-005695-14.

The Paisley Caves in Oregon record the oldest directly dated human remains (DNA) in the Western Hemisphere. More than 100 high-precision radiocarbon dates show that deposits containing artifacts and coprolites ranging in age from 12,450 to 2295 (14)C years ago are well stratified. Western Stemmed projectile points were recovered in deposits dated to 11,070 to 11,340 (14)C years ago, a time contemporaneous with or preceding the Clovis technology. There is no evidence of diagnostic Clovis technology at the site. These two distinct technologies were parallel developments, not the product of a unilinear technological evolution. "Blind testing" analysis of coprolites by an independent laboratory confirms the presence of human DNA in specimens of pre-Clovis age. The colonization of the Americas involved multiple technologically divergent, and possibly genetically divergent, founding groups.

Background: Cell therapy is an emerging and exciting novel treatment option for cardiovascular disease that relies on the delivery of functional cells to their target site. Monitoring and tracking cells to ensure tissue delivery and engraftment is a critical step in establishing clinical and therapeutic efficacy. The study aims were (1) to develop a Good Manufacturing Practice-compliant method of labeling competent peripheral blood mononuclear cells with superparamagnetic particles of iron oxide (SPIO), and (2) to evaluate its potential for magnetic resonance cell tracking in humans., Methods and Results: Peripheral blood mononuclear cells 1-5 × 10(9) were labeled with SPIO. SPIO-labeled cells had similar in vitro viability, migratory capacity, and pattern of cytokine release to unlabeled cells. After intramuscular administration, up to 10(8) SPIO-labeled cells were readily identifiable in vivo for at least 7 days using magnetic resonance imaging scanning. Using a phased-dosing study, we demonstrated that systemic delivery of up to 10(9) SPIO-labeled cells in humans is safe, and cells accumulating in the reticuloendothelial system were detectable on clinical magnetic resonance imaging. In a healthy volunteer model, a focus of cutaneous inflammation was induced in the thigh by intradermal injection of tuberculin. Intravenously delivered SPIO-labeled cells tracked to the inflamed skin and were detectable on magnetic resonance imaging. Prussian blue staining of skin biopsies confirmed iron-laden cells in the inflamed skin., Conclusions: Human peripheral blood mononuclear cells can be labeled with SPIO without affecting their viability or function. SPIO labeling for magnetic resonance cell tracking is a safe and feasible technique that has major potential for a range of cardiovascular applications including monitoring of cell therapies and tracking of inflammatory cells. Clinical Trial Registration- URL: http://www.clinicaltrials.gov; Unique identifier: NCT00972946, NCT01169935.

Aims: The aim of this study was to investigate the effects of liver X receptors (LXRs)-β preferential activation by LXR-623 (WAY-252623), a novel LXRs agonist, on plaque progression/regression in a rabbit model of advanced atherosclerosis., Methods and Results: Advanced atherosclerosis was induced in New Zealand White Rabbits (n= 41). At the end of atherosclerosis induction, animals underwent a baseline magnetic resonance imaging (MRI) and were randomized to receive LXR-623 (1.5, 5, or 15 mg/kg/day), simvastatin (5 mg/kg/day), or placebo. The combination of LXR-1.5/simvastatin was also tested. After a final MRI, animals were euthanized and their aortas processed for further analysis. Simvastatin significantly reduced lesion progression (-25%; P< 0.01) in comparison with the placebo group. A similar effect was observed in the LXR-1.5 and -5 groups. A significant regression (16.5%; P< 0.01) of existing atherosclerosis was observed in the LXR-1.5/simvastatin group. Histological and molecular analysis showed plaque stabilization in the animals treated with the LXR-1.5 and -5, and LXR-1.5/simvastatin. The effects of LXR-623 were observed in the presence of a non-significant effect on total-cholesterol, low-density lipoproteins-cholesterol, and triglyceride levels., Conclusion: The results of the present study show that LXR-623 significantly reduces the progression of atherosclerosis and induces plaque regression in combination with simvastatin. These observations could drive future development of novel anti-atherosclerotic therapeutic approaches.

Background: The Badimon chamber is a clinical ex vivo model of thrombosis that mimics flow conditions within the coronary circulation of man. The aims of this study were to characterise thrombus formation in the chamber and evaluate its reproducibility., Methods: Using blood from 24 healthy human volunteers, thrombus formation was assessed at low and high shear rates with porcine aortic tunica media as the thrombogenic substrate. Thrombus area was measured histomorphometrically. Reproducibility was assessed by paired measurements made both within and between days. Platelet activation was assessed before and at selected points within the extracorporeal circuit using flow cytometry, and fibrin content and distribution within the thrombus were assessed by immunohistochemistry., Results: Total thrombus area was highly reproducible within and between days in the low shear ([mean thrombus area, mean difference ± SEM] 8,018μm(2), 58±204μm(2) and 8,177μm(2), -154±168μm(2) respectively) and high shear chambers (11,802μm(2), -52±175μm(2) and 11,877μm(2), 220±181μm(2) respectively). Total thrombus area was greater in the high compared to the low shear chamber (11,970±285μm(2)versus 7,892±298μm(2); P<0.0001). Transit through the extracorporeal circuit did not result in platelet activation which was only detected after blood passed across the perfusion chambers (P=0.02 for platelet-monocyte aggregate formation and P=0.05 for P-selectin expression). Thrombus in the low shear chamber contained a greater proportion of fibrin (25.0±6.0% versus 8.3±1.6%, P<0.001)., Conclusions: The Badimon chamber provides a highly reproducible technique for the assessment of ex vivo platelet-rich thrombus formation in man., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

In cardiovascular disease rupture of a vulnerable atherosclerotic plaque is the major causative factor of acute coronary syndromes, myocardial infarction and stroke, and can ultimately lead to death. Identification of biomarkers that could accurately predict the risk of plaque rupture would be a significant advance in guiding treatment of patients with this disease, The use of these biomarkers would also facilitate the development of new drugs to treat cardiovascular disease, particularly those that act through novel mechanisms. There is currently a lack of specific biomarkers for vulnerable plaque, and thus, it is an area of intense research including the concepts of live detection versus retrospective characterization, molecular imaging, and biochemical biomarker discovery. This review will focus on recent advances on both imaging and circulating molecular biomarkers in atherosclerosis. The use of combinations of different imaging modalities (such as molecular, functional, and anatomical) and modalities with circulating/biochemical markers is the current trend and will likely provide the most useful information for the assessment of the vulnerability of atherosclerotic plaques.

The electron field-emission (FE) characteristics of functionalized single-walled carbon-nanotube (CNT)-polymer composites produced by solution processing are reported. It is shown that excellent electron emission can be obtained by using as little as 0.7% volume fraction of nanotubes in the composite. Furthermore by tailoring the nanotube concentration and type of polymer, improvements in the charge transfer through the composite can be obtained. The synthesis of well-dispersed randomly oriented nanotube-polymer composites by solution processing allows the development of CNT-based large area cathodes produced using a scalable technology. The relative insensitivity of the cathode's FE characteristics to the electrical conductivity of the composite is also discussed.

Generation of NO by nitric oxide synthase (NOS) is implicated in gamete interaction and fertilisation. Exposure of human spermatozoa to NO donors caused mobilisation of stored Ca(2+) by a mechanism that did not require activation of guanylate cyclase but was mimicked by S-nitroso-glutathione (GSNO; an S-nitrosylating agent). Application of dithiothreitol, to reduce protein -SNO groups, rapidly reversed the actions of NO and GSNO on [Ca(2+)](i). The effects of NO, GSNO and dithiothreitol on sperm protein S-nitrosylation, assessed using the biotin switch method, closely paralleled their actions on [Ca(2+)](i). Immunofluorescent staining revealed constitutive and inducible NOS in human oviduct and cumulus (the cellular layer investing the oocyte). 4,5-diaminofluorescein (DAF) staining demonstrated production of NO by these tissues. Incubation of human sperm with oviduct explants induced sperm protein S-nitrosylation resembling that induced by NO donors and GSNO. Progesterone (a product of cumulus cells) also mobilises stored Ca(2+) in human sperm. Pre-treatment of sperm with NO greatly enhanced the effect of progesterone on [Ca(2+)](i), resulting in a prolonged increase in flagellar excursion. We conclude that NO regulates mobilisation of stored Ca(2+) in human sperm by protein S-nitrosylation, that this action is synergistic with that of progesterone and that this synergism is potentially highly significant in gamete interactions leading to fertilisation.

The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.

The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.

Tetrabromobisphenol A (TBBPA) is a commonly used brominated flame retardant (BFR) utilized to reduce the flammability of a variety of products. Studies have indicated that a number of BFRs are becoming widely distributed within the environment and are bio-accumulating within organisms. There has been much speculation that a variety of phenolic pollutants (including compounds chemically related to TBBPA, such as bisphenol A) may cause endocrine disruption and Ca2+ dysregulation in cells involved in spermatogenesis. In this study we therefore investigate the effects of TBBPA on mouse TM4 Sertoli cells (essential for sperm development). Results show that TBBPA increases Ca2+ within these cells in the 5-60 microM concentration range (EC50, 21 microM). TBBPA also causes cell death (LC50, 18 microM) partly via apoptosis, involving Ca2+-dependent mitochondrial depolarisation. Studies on intracellular Ca2+ transporters shows that TBBPA can inhibit sarcoplasmic/endoplasmic reticulum Ca2+-ATPases (SERCA) at low concentrations (IC50, 0.4 to 1.2 microM) and also activate the Ryanodine receptor Ca2+ channel within the 0.4-4 microM concentration range. Therefore these studies suggest that the cytotoxic effects of TBBPA on cells is partly due to dysregulation of Ca2+ signalling, by directly affecting Ca2+ transport proteins.

Nuclear hormone receptors, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), and the farnesoid X receptor (FXR), are transcription factors involved in the regulation of essential metabolic functions, including glucose and lipid metabolism, reverse cholesterol transport, and the regulation of bile acids. This review summarizes new developments in the use of PPAR, LXR and FXR agonists for the treatment of obesity and cardiovascular diseases, including dyslipidemia and atherosclerosis. Currently available drugs and future areas of research for new therapies are also discussed.

To examine the relationship between symptoms of urinary incontinence (UI) and mode of delivery, parity, and birth weight, data were obtained from a population-based random sample of 3,205 black, Hispanic, and white women age 30-79 in the Boston Area Community Health Survey. Measures include UI symptoms [>or=3 (moderate/severe) Sandvik's severity index]; reproductive history [live birth(s), no live births, never pregnant]; mode of delivery for live births (>or=1 vaginal birth, cesarean delivery only); parity (1, 2, >or=3); and maximum birth weight of live births (<4,000 g, >or=4,000 g). Using logistic regression, women having >or=1 vaginal delivery had twice the odds of UI compared to women with no pregnancies (P = 0.002) or only cesarean deliveries (P = 0.032). There was no difference in odds of UI between cesarean delivery only and never pregnant, by parity or birth weight. Vaginal delivery contributes to risk of UI for black, Hispanic, and white women.

A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain.

The synthesis of the first high specific activity S-35-labeled hERG radioligand, [(35)S]MK-0499, for use in HTS assays of drug candidates for hERG interaction is described. The radioligand is prepared by [(35)S]sulfonylation of a high diastereomeric excess (de) aniline precursor prepared from unlabeled MK-0499.

Atypical glandular cells (AGC) in Papanicolaou (Pap) smears can be associated with premalignant and malignant cervical and endometrial lesions. AGC is difficult to diagnose in pregnancy due to confusion with normal cellular changes that accompany graviditas. While guidelines have been established for management of AGC cases in the non-pregnant patient, special considerations are required when this is discovered during a pregnancy. A routine Pap smear performed on a 29-year-old woman being seen for a history of infertility yielded AGC and a high-grade squamous intraepithelial lesion. The patient achieved pregnancy 1 month later. Satisfactory colposcopic exam was performed with cytobrush sampling of the endocervical canal, in addition to 2 exocervical biopsies at 11 weeks gestation. Positive diagnosis of endocervical adenocarcinoma in situ resulted in a risk-informed decision to proceed with a cold knife conization of the cervix. Final pathology showed complete resection of the lesion with negative margins and an additional area of squamous dysplasia (cervical intraepithelial neoplasia, grade II to III). Appropriate follow-up was recommended. AGC found upon Pap smear during a pregnancy can be associated with significant pathology for which an aggressive management approach is warranted.

Background: Infectious morbidity after tension-free vaginal tape (TVT) treatment of urinary stress incontinence may be a potential concern., Case: A 53-year-old obese woman with a 7-year history of urinary incontinence consented to TVT placement. Two days after discharge the patient presented with suspected cellulitis. Dicloxacillin, ciprofloxacin, ampicillin/sulbactam, and metronidazole were ineffective. Removal of the tape, surgical debridement, dressing changes, ceftriaxone, and clindamycin followed by levofloxacin and metronidazole, repeat wound debridement, and vacuum assisted closure were required. Frozen section revealed gangrenous soft tissue with areas of skin necrosis, but no fasciitis., Conclusion: This is the first case of necrotizing surgical site infection after TVT placement. Infectious morbidity risks need to be considered in these procedures.

The mineralocorticoid aldosterone plays an important role in the regulation of plasma electrolyte homeostasis. Exposure of acutely isolated rat adrenal zona glomerulosa cells to elevated K(+) activates voltage-gated calcium channels and initiates a calcium-dependent increase in aldosterone synthesis. We developed a novel 96-well format aldosterone secretion assay to rapidly evaluate the effect of known T- and L-type calcium channel antagonists on K(+)-stimulated aldosterone secretion and better define the role of voltage-gated calcium channels in this process. Reported T-type antagonists, mibefradil and Ni(2+), and selected L-type antagonist dihydropyridines, inhibited K(+)-stimulated aldosterone synthesis. Dihydropyridine-mediated inhibition occurred at concentrations which had no effect on rat alpha1H T-type Ca(2+) currents. In contrast, below 10 microM, the L-type antagonists verapamil and diltiazem showed only minimal inhibitory effects. To examine the selectivity of the calcium channel antagonist-mediated inhibition, we established an aldosterone secretion assay in which 8Br-cAMP stimulates aldosterone secretion independent of extracellular calcium. Mibefradil remained inhibitory in this assay, while the dihydropyridines had only limited effects. Taken together, these data demonstrate a role for the L-type calcium channel in K(+)-stimulated aldosterone secretion. Further, they confirm the need for selective T-type calcium channel antagonists to better address the role of T-type channels in K(+)-stimulated aldosterone secretion.

D-serine is present in the mammalian central nervous system, where it acts as one of the co-activators of N-methyl-D aspartate receptors. Synthesis of D-serine is catalyzed by the serine racemase enzyme. The current studies report on the isolation of a cDNA encoding a human serine racemase (SRR) from the human neuronal like cell line, NT2N. The SRR gene was localized on chromosome 17q13. The full-length cDNA has 1020 nucleotides which encode for a protein of 340 amino acids. The human protein shares 89% sequence identity with the mouse serine racemase. Human embryonic kidney 293 cells transiently transfected with this SRR gene were able to produce d-serine, indicating that the sequence encodes for an active enzyme. In Northern blot analysis the SRR mRNA was expressed in human brain, heart, skeletal muscle, kidney and liver tissues. Different splice forms of SRR were present in the peripheral tissues. Transcripts of at least three different sizes were present in heart and kidney, while in Western blot analysis multiple bands of different sizes were observed. Immunohistochemical studies, using a polyclonal anti-human serine racemase antibody, revealed a peripheral expression of serine racemase protein in human cardiac myocytes and convoluted tubules of the kidney. Experiments in non-human primate brain demonstrated the localization of SRR in amygdala nuclei, cortex, thalamus and hippocampus. Co-localization studies in the hippocampus demonstrated the exclusive expression of serine racemase in glial cells. The cloning of a functional human serine racemase and its expression in central nervous system of primates support a role for D-serine in neuronal activity. Furthermore, its presence in human periphery such as in heart and kidney suggest a potential biological role for D-serine in the regulation of N-methyl-D-aspartate (NMDA) receptor activity in these peripheral organs as well.

Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.

The current studies describe a new, robust cell-based functional assay useful to characterize L-type voltage-dependent calcium channels and their antagonists. The basis of this assay is measurement in plate format of Ca2+ influx through the L-type Ca2+ channel complex (alpha1C, alpha2delta, and beta2a subunits) in response to potassium-mediated depolarization; EC(50)=11 mM [K+](o). The Ca2+ influx was inhibited by the L-type Ca2+ channel antagonist, nimodipine; IC(50)=59 nM. These cells were also transfected with the Kir2.3 inward rectifier K(+) channel, which allows for changing the cell membrane potential by modulation of extracellular [K](o); -65 mV in physiological [K](o) and -28 mV in 30 mM [K](o) containing buffer. The conformational state of the voltage-sensitive Ca2+ channel is altered under these different conditions. Under the depolarized condition, nimodipine was a more potent antagonist, inhibiting Ca2+ influx with an IC(50) value of 3 nM. The results demonstrate that the interaction of nimodipine and other antagonists with the channel is modulated by changes in membrane potential and thus the state of the channel. Overall, this novel assay can be used to identify state-dependent calcium channel antagonists and should be useful for evaluating state-dependent inhibitory potency of a large number of samples.

Establishment of stable cell lines that constitutively express Ca(2+) channels at high density and that are useful for in vitro studies may be complicated by problems with seal quality and duration during whole-cell patch-clamp electrophysiology. The current studies describe the generation and characterization of cells that express the human alpha1H T-type Ca(2+) channel under the control of a tetracycline-inducible expression system. Western blot and immunostaining studies revealed that expression of the alpha1H protein occurred only in the presence of tetracycline. Using the whole-cell patch-clamp method, the cells displayed peak inward currents of 1.15 +/- 0.14 nA in response to voltage-clamp steps. The T-type Ca(2+) current was inhibited by the T-type Ca(2+) channel antagonist, mibefradil, with an IC(50) of 160 nM. This cell line, with inducible channel expression, sealed with longer duration during whole-cell patch-clamp recording when compared with a cell line that constitutively expresses the alpha1H Ca(2+) channel. Ca(2+) influx through this channel could also be detected after the addition of extracellular Ca(2+). The amount of Ca(2+) influx was dependent on the [Ca](o) with an EC(50) of 4 mM. The Ca(2+) influx was also inhibited by mibefradil with a potency (IC(50) = 183 nM) similar to that observed in the voltage-clamp studies. Overall, this inducible alpha1H Ca(2+) channel-expressing cell line is useful for the study of human T-type Ca(2+) channel function, and offers advantages over a similar cell line that constitutively expresses the channel.

Treatment of pain and inflammation associated with dysmenorrhea, endometriosis, ovarian cancers and operative procedures is an ongoing challenge in gynecology. Understanding the roles of prostanoids and estrogen in these conditions and appropriate treatment approaches have advanced beyond traditional nonsteroidal anti-inflammatory drugs. In this article, the author describes some of the basic mechanisms of nonspecific nonsteroidal anti-inflammatory drugs and newer cyclooxygenase-2 inhibitors, especially as they are used in the obstetrics/gynecology practice.

The American College of Obstetricians and Gynecologists clinical indicator for unplanned return to the operating room during the same admission in an obstetrics and gynecology residency is reviewed in this article. A retrospective chart review of all gynecologic surgeries during a 3-year period was evaluated for this indicator. An incidence of 0.03% was noted, with 3 of 1,492 procedures meeting the definition of this indicator. The incidence of this clinical indicator is uncommon in a community hospital-based obstetrics and gynecology residency.

A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.

Background: Venous thromboembolism (VTE) has historically remained a risk factor for obstetric patients, particularly those requiring cesarean section. The objective of this survey was to assess the response of general obstetricians to risk factor considerations for VTE prophylaxis and cesarean section., Methods: A survey regarding VTE prophylaxis and cesarean section was sent to 113 obstetricians practicing in suburban Chicago and northern Wisconsin., Results: There were 51 responses (45%) to the survey. Most respondents do not routinely use VTE prophylaxis for cesarean section in patients who may have one or more risk factors., Conclusion: There appears to be lack of consensus or appreciation for VTE and prophylaxis for cesarean section. Further studies and education are warranted.

We established HEK-293 cell lines that stably express functional canine ether-à-go-go-related gene (cERG) K(+) channels and examined their biophysical and pharmacological properties with whole cell patch clamp and (35)S-labeled MK-499 ([(35)S]MK-499) binding displacement. Functionally, cERG current had the hallmarks of cardiac delayed rectifier K(+) current (I(Kr)). Channel opening was time- and voltage dependent with threshold near -40 mV. The half-maximum activation voltage was -7.8 +/- 2.4 mV at 23 degrees C, shifting to -31.9 +/- 1.2 mV at 36 degrees C. Channels activated with a time constant of 13 +/- 1 ms at +20 mV, showed prominent inward rectification at depolarized potentials, were highly K(+) selective (Na(+)-to-K(+) permeability ratio = 0.007), and were potently inhibited by I(Kr) blockers. Astemizole, terfenadine, cisapride, and MK-499 inhibited cERG and human ERG (hERG) currents with IC(50) values of 1.3, 13, 19, and 15 nM and 1.2, 9, 14, and 21 nM, respectively, and competitively displaced [(35)S]MK-499 binding from cERG and hERG with IC(50) values of 0.4, 12, 35, and 0.6 nM and 0.8, 5, 47, and 0.7 nM, respectively. cERG channels had biophysical properties appropriate for canine action potential repolarization and were pharmacologically sensitive to agents known to prolong QT. A novel MK-499 binding assay provides a new tool to detect agents affecting ERG channels.

The synthesis and biological evaluation of a series of nonpeptidic small molecule antagonists of the human platelet thrombin receptor (PAR-1) are described. Optimization of the 5-amino-3-arylisoxazole lead resulted in an approximate 100-fold increase in potency. The most potent of these compounds (54) inhibits platelet activation with IC(50)s of 90 nM against the thrombin receptor agonist peptide (TRAP) and 510 nM against thrombin as the agonist. Further, antagonist 54 fully blocks platelet aggregation stimulated by 1 nM thrombin for 10 min.