Effect of Aging and a Dual Orexin Receptor Antagonist on Sleep Architecture and Non-REM Oscillations Including an REM Behavior Disorder Phenotype in the PS19 Mouse Model of Tauopathy.

The impact of tau pathology on sleep microarchitecture features, including slow oscillations, spindles, and their coupling, has been understudied, despite the proposed importance of these electrophysiological features toward learning and memory. Dual orexin receptor antagonists (DORAs) are known to promote sleep, but whether and how they affect sleep microarchitecture in the setting of tauopathy is unknown. In the PS19 mouse model of tauopathy MAPT (microtubule-associated protein tau) P301S (both male and female), young PS19 mice 2-3 months old show a sleep electrophysiology signature with markedly reduced spindle duration and power and elevated slow oscillation (SO) density compared with littermate controls, although there is no significant tau hyperphosphorylation, tangle formation, or neurodegeneration at this age. With aging, there is evidence for sleep disruption in PS19 mice, characterized by reduced REM duration, increased non-REM and REM fragmentation, and more frequent brief arousals at the macrolevel and reduced spindle density, SO density, and spindle-SO coupling at the microlevel. In ∼33% of aged PS19 mice, we unexpectedly observed abnormal goal-directed behaviors in REM, including mastication, paw grasp, and forelimb/hindlimb extension, seemingly consistent with REM behavior disorder (RBD). Oral administration of DORA-12 in aged PS19 mice increased non-REM and REM duration, albeit with shorter bout lengths, and increased spindle density, spindle duration, and SO density without change to spindle-SO coupling, power in either the SO or spindle bands, or the arousal index. We observed a significant effect of DORA-12 on objective measures of RBD, thereby encouraging future exploration of DORA effects on sleep-mediated cognition and RBD treatment.SIGNIFICANCE STATEMENT The specific effect of tauopathy on sleep macroarchitecture and microarchitecture throughout aging remains unknown. Our key findings include the following: (1) the identification of a sleep EEG signature constituting an early biomarker of impending tauopathy; (2) sleep physiology deteriorates with aging that are also markers of off-line cognitive processing; (3) the novel observation that dream enactment behaviors reminiscent of RBD occur, likely the first such observation in a tauopathy model; and (4) a dual orexin receptor antagonist is capable of restoring several of the sleep macroarchitecture and microarchitecture abnormalities.

A programmable two-qubit quantum processor in silicon.

Now that it is possible to achieve measurement and control fidelities for individual quantum bits (qubits) above the threshold for fault tolerance, attention is moving towards the difficult task of scaling up the number of physical qubits to the large numbers that are needed for fault-tolerant quantum computing. In this context, quantum-dot-based spin qubits could have substantial advantages over other types of qubit owing to their potential for all-electrical operation and ability to be integrated at high density onto an industrial platform. Initialization, readout and single- and two-qubit gates have been demonstrated in various quantum-dot-based qubit representations. However, as seen with small-scale demonstrations of quantum computers using other types of qubit, combining these elements leads to challenges related to qubit crosstalk, state leakage, calibration and control hardware. Here we overcome these challenges by using carefully designed control techniques to demonstrate a programmable two-qubit quantum processor in a silicon device that can perform the Deutsch-Josza algorithm and the Grover search algorithm-canonical examples of quantum algorithms that outperform their classical analogues. We characterize the entanglement in our processor by using quantum-state tomography of Bell states, measuring state fidelities of 85-89 per cent and concurrences of 73-82 per cent. These results pave the way for larger-scale quantum computers that use spins confined to quantum dots.

U2AF2 variant in a patient with developmental delay, dysmorphic features, and epilepsy.

Variants in the RNA binding protein (RBP) U2AF2 are hypothesized to cause a novel neurodevelopmental disorder. Here, we report a patient with a de novo missense variant in U2AF2, the second case report of the same variant, and third case report overall. The patient in this report has a history of global developmental delay, dysmorphic features, and epilepsy. This presentation is consistent with the previous case report with the same U2AF2 variant and with a recent case report of another U2AF2 variant, strengthening the evidence that variants in U2AF2 are the cause of a novel neurodevelopmental disorder.

The stochastic wave function method for diffusion of alkali atoms on metallic surfaces.

The stochastic wave function method is proposed to study the diffusion regimes of alkali atoms on metallic surfaces. The Lindblad approach, based on the microscopic Hamiltonian information in the Caldeira-Leggett model, is presented and numerical calculations of the dynamics are carried out to characterize surface diffusion for two different systems: Na-Cu(111) and Li-Cu(111). Calculations of the intermediate scattering function for an isolated adsorbate are compared, in the Brownian limit, with results deduced from helium spin-echo (HeSE) experiments after reducing them to single adsorbate dynamics. To illustrate the method we present the dependence on momentum transfer and the temperature dependency. Results show that the experiment can be described at a quantitative level by the 1-D quantum model (reduced dimensionality).

Observation of diffuse scattering in scanning helium microscopy.

In understanding the nature of contrast in the emerging field of neutral helium microscopy, it is important to identify if there is an atom-surface scattering distribution that can be expected to apply broadly across a range of sample surfaces. Here we present results acquired in a scanning helium microscope (SHeM) under typical operating conditions, from a range of surfaces in their native state, i.e. without any specialist sample preparation. We observe diffuse scattering, with an approximately cosine distribution centred about the surface normal. The 'cosine-like' distribution is markedly different from those distributions observed from the well-prepared, atomically pristine, surfaces typically studied in helium atom scattering experiments. Knowledge of the typical scattering distribution in SHeM experiments provides a starting basis for interpretation of topographic contrast in images, as well as a reference against which more exotic contrast mechanisms can be compared.

Review of the MRI brain findings of septo-optic dysplasia.

AIM: To report the magnetic resonance imaging (MRI) findings from a retrospective case analysis of children with septo-optic dysplasia (SOD), a rare congenital disorder characterised by any combination of midline brain defects, optic nerve hypoplasia (ONH), and hypothalamic-pituitary dysfunction. MATERIALS AND METHODS: SOD was defined radiologically as complete or partial septum pellucidum (SP) absence with hypoplasia of at least one of the optic nerves and/or chiasm. Local MRI databases were searched for SOD cases in children over an 18-year period, and studies reviewed by two consultant paediatric neuroradiologists. The extent of structural SP, optic nerve, chiasm, and hypothalamic-pituitary involvement was recorded, along with coexisting brain abnormalities. RESULTS: Forty-eight cases of SOD were found; 44/48 (92%) demonstrated complete SP absence whereas 4/48 (8%) had partial absence. Eight of 48 cases (17%) exhibited unilateral ONH. Fifty-one percent of cases, where the pituitary was identified on MRI, demonstrated a structural pituitary abnormality, which included an ectopic posterior bright spot in 6%. The olfactory nerves were hypoplastic in 5/48 cases (10%). Twenty-seven of the 48 cases (56%) had another brain abnormality, resulting from some form of cortical formation abnormality/schizencephaly in 21/48 (44%). CONCLUSION: A high rate of associated brain abnormalities was found in the present cohort, including structural pituitary abnormalities in 51% and cortical formation abnormalities/schizencephaly in 44%. This suggests there is not a single cause for SOD, rather SOD is the phenotypic end point from multiple aetiological events. Individual children with SOD may have coexisting intracranial abnormalities, and, hence, high-quality MRI is required in all.

Sexual risk and HIV testing disconnect in men who have sex with men (MSM) recruited to an online HIV self-testing trial.

OBJECTIVES: We report the frequency of previous HIV testing at baseline in men who have sex with men (MSM) who enrolled in an HIV self-testing (HIVST) randomized controlled trial [an HIV self-testing public health intervention (SELPHI)]. METHODS: Criteria for enrolment were age ≥ 16 years, being a man (including trans men) who ever had anal intercourse (AI) with a man, not being known to be HIV positive and having consented to national HIV database linkage. Using online survey baseline data (2017-2018), we assessed associations with never having tested for HIV and not testing in the previous 6 months, among men who reported at least two recent condomless AI (CAI) partners. RESULTS: A total of 10 111 men were randomized; the median age was 33 years [interquartile range (IQR) 26-44 years], 89% were white, 20% were born outside the UK, 0.8% were trans men, 47% were degree educated, and 8% and 4% had ever used and were currently using pre-exposure prophylaxis (PrEP), respectively. In the previous 3 months, 89% reported AI and 72% reported CAI with at least one male partner. Overall, 17%, 33%, 54%, and 72% had tested for HIV in the last 3 months, 6 months, 12 months and 2 years, respectively; 13% had tested more than 2 years ago and 15% had never tested. Among 3972 men reporting at least two recent CAI partners, only 22% had tested in the previous 3 months. Region of residence and education level were independently associated with recent HIV testing. Among current PrEP users, 15% had not tested in the previous 6 months. CONCLUSIONS: Most men in SELPHI, particularly those reporting at least two CAI partners and current PrEP users, were not testing in line with current UK recommendations. The results of the trial will inform whether online promotion of HIVST addresses ongoing testing barriers.

HIV self-testing intervention experiences and kit usability: results from a qualitative study among men who have sex with men in the SELPHI (Self-Testing Public Health Intervention) randomized controlled trial in England and Wales.

OBJECTIVES: SELPHI (HIV Self-Testing Public Health Intervention) is the largest randomized controlled trial (RCT) of HIV self-testing (HIVST) in a high-income setting to date, and has recruited 10 000 men who have sex with men (cis- and transgender) and transgender women who have sex with men. This qualitative substudy aimed to explore how those utilizing self-tests experience HIVST and the implications for further intervention development and scale-up. This is the first qualitative study in Europe investigating experiences of HIVST among intervention users, and the first globally examining the experience of using blood-based HIVST. METHODS: Thirty-seven cisgender MSM SELPHI participants from across England and Wales were purposively recruited to the substudy, in which semi-structured interviews were used to explore testing history, HIVST experiences and intervention preferences. Interviews were audio-recorded, transcribed and analysed through a framework analysis. RESULTS: Men accessed the intervention because HIVST reduced barriers related to convenience, stigma and privacy concerns. Emotional responses had direct links to acceptability. Supportive intervention components increased engagement with testing and addressed supportive concerns. HIVST facilitated more frequent testing, with the potential to reduce sexually transmitted infection (STI) screening frequency. Substudy participants with an HIV-positive result (n = 2) linked to care promptly and reported very high acceptability. Minor adverse outcomes (n = 2; relationship discord and fainting) did not reduce acceptability. Ease of use difficulties were with the lancet and the test processing stage. CONCLUSIONS: Intervention components shaped acceptability, particularly in relation to overcoming a perceived lack of support. The intervention was broadly acceptable and usable; participants expressed an unexpected degree of enthusiasm for HIVST, including those with HIV-positive results and individuals with minor adverse outcomes.

Quantum control and process tomography of a semiconductor quantum dot hybrid qubit.

The similarities between gated quantum dots and the transistors in modern microelectronics--in fabrication methods, physical structure and voltage scales for manipulation--have led to great interest in the development of quantum bits (qubits) in semiconductor quantum dots. Although quantum dot spin qubits have demonstrated long coherence times, their manipulation is often slower than desired for important future applications, such as factoring. Furthermore, scalability and manufacturability are enhanced when qubits are as simple as possible. Previous work has increased the speed of spin qubit rotations by making use of integrated micromagnets, dynamic pumping of nuclear spins or the addition of a third quantum dot. Here we demonstrate a qubit that is a hybrid of spin and charge. It is simple, requiring neither nuclear-state preparation nor micromagnets. Unlike previous double-dot qubits, the hybrid qubit enables fast rotations about two axes of the Bloch sphere. We demonstrate full control on the Bloch sphere with π-rotation times of less than 100 picoseconds in two orthogonal directions, which is more than an order of magnitude faster than any other double-dot qubit. The speed arises from the qubit's charge-like characteristics, and its spin-like features result in resistance to decoherence over a wide range of gate voltages. We achieve full process tomography in our electrically controlled semiconductor quantum dot qubit, extracting high fidelities of 85 per cent for X rotations (transitions between qubit states) and 94 per cent for Z rotations (phase accumulation between qubit states).

Effect of the Smart Moms intervention on targeted mediators of change in child sugar-sweetened beverage intake.

OBJECTIVE: Few parent-targeted interventions have examined the mechanisms of action by which the intervention changes child behavior. The purpose of this study was to test the theoretical and behavioral mediators of the Smart Moms intervention on changes in child sugar-sweetened beverage and juice (SSB/juice) consumption. STUDY DESIGN: This is a secondary mediation analysis of data from a 6-month randomized controlled trial (N = 51 mother-child dyads) of a mobile phone-based program to reduce child SSB/juice intake compared with a waitlist control group. METHODS: Linear mixed models compared changes in intervention targets from baseline to 3 months between treatment groups. Intervention targets that changed significantly between groups were tested in a multiple mediation model to evaluate their significance as mediators of change in child SSB/juice at 6 months. RESULTS: Maternal beverage consumption but no other behavioral or theoretical intervention targets mediated the effect of the intervention on the reduction in child SSB/juice at 6 months. There were few mediators of the intervention on child SSB/juice change. CONCLUSION: Greater longitudinal research is needed to understand predictors of child dietary changes to inform future intervention efforts. In addition, a greater focus on the measurement of theoretical constructs in family-based child obesity prevention research is needed.

Dynamics of sleep spindles and coupling to slow oscillations following motor learning in adult mice.

Sleep spindles have been implicated in motor learning in human subjects, but their occurrence, timing in relation to cortical slow oscillations, and relationship to offline gains in motor learning have not been examined in animal models. In this study, we recorded EEG over bilateral primary motor cortex in conjunction with EMG for 24 h following a period of either baseline handling or following rotarod motor learning to monitor sleep. We measured several biophysical properties of sleep spindles and their temporal coupling with cortical slow oscillations (SO, <1 Hz) and cortical delta waves (1-4 Hz). Following motor learning, we found an increase in spindles during an early period of NREM sleep (1-4 h) without changes to biophysical properties such as spindle power, peak frequency and coherence. In this same period of early NREM sleep, both SO and delta power increased after motor learning. Notably, a vast majority of spindles were associated with minimal SO power, but in the subset that were associated with significant SO power (>1 z-score above the population mean), spindle-associated SO power was greater in spindles following motor learning compared to baseline sleep. Also, we did not observe a group-level preferred phase in spindle-SO or spindle-delta coupling. While SO power alone was not predictive of motor performance in early NREM sleep, both spindle density and the difference in the magnitude of the mean resultant vector length of the phase angle for SO-associated spindles, a measure of its coupling precision, were positively correlated with offline change in motor performance. These findings support a role for sleep spindles and their coupling to slow oscillations in motor learning and establish a model in which spindle timing and the brain circuits that support offline plasticity can be mechanistically explored.

Highly tunable thiosulfonates as a novel class of cysteine protease inhibitors with anti-parasitic activity against Schistosoma mansoni.

The development of a new class of cysteine protease inhibitors utilising the thiosulfonate moiety as an SH specific electrophile is described. This moiety has been introduced into suitable amino acid derived building blocks, which were incorporated into peptidic sequences leading to very potent i.e. sub micromolar inhibitors of the cysteine protease papain in the same range as the vinyl sulfone based inhibitor K11777. Therefore, their inhibitory effect on Schistosoma mansoni, a human blood parasite, that expresses several cysteine proteases, was evaluated. The homophenylalanine side chain containing compounds 27-30 and especially 36 showed promising activities compared with K11777 and warrant further investigations of these peptidic thiosulfonate inhibitors as new potential anti-parasitic compounds.

Concordance Rates Between Resident-Performed Ultrasound Measurements and Certified Sonographer Measurements.

OBJECTIVES: To evaluate the accuracy of ultrasound (US) estimated fetal weight (EFW) measurement compared with neonatal birth weight when performed by residents versus certified sonographers. The hypothesis tested was that residents and certified sonographers would not differ significantly in EFW or in EFW compared with neonatal birth weight. METHODS: A retrospective chart review of 142 inpatients from July 2010 to May 2011 was conducted. Ultrasound examinations were performed by a resident physician and a certified sonographer within 7 days after the resident. Standard US measurements obtained were head circumference, biparietal diameter, abdominal circumference, femur length, estimated gestational age, and EFW. Gestational age ranged from 20 to 39 weeks. The time from US to delivery, residency year, and birth weight were collected. Measurements were compared by paired t tests, the Wilcoxon signed rank test, and repeated-measures analysis of variance. RESULTS: The US EFW by residents and sonographers showed excellent concordance with each other regardless of the neonatal birth weight. The resident and sonographer EFW each showed excellent concordance with the neonatal birth weight, and this concordance did not differ significantly between residents and sonographers for neonates weighing less than 1000 g (P = .61) and neonates weighing greater than or equal to 1000 to less than 2000 g (P = .93). The resident EFW (P < .05) and sonographer EFW (P < .01), however, were less than the neonatal birth weight for larger neonates (≥2000 g), but the degree of underestimation was not significantly different between residents and sonographers (P = .51). CONCLUSIONS: Accurate EFW is critical for prenatal management. These data support the value of a dedicated month of US training in residency programs.

Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics.

Primary immunodeficiencies (PIDs) are rare monogenic inborn errors of immunity that result in impairment of functions of the human immune system. PIDs have a broad phenotype with increased morbidity and mortality, and treatment choices are often complex. With increased accessibility of next-generation sequencing (NGS), the rate of discovery of genetic causes for PID has increased exponentially. Identification of an underlying monogenic diagnosis provides important clinical benefits for patients with the potential to alter treatments, facilitate genetic counselling, and pre-implantation diagnostics. We investigated a NGS PID panel of 242 genes within clinical care across a range of PID phenotypes. We also evaluated Phenomizer to predict causal genes from human phenotype ontology (HPO) terms. Twenty-seven participants were recruited, and a total of 15 reportable variants were identified in 48% (13/27) of the participants. The panel results had implications for treatment in 37% (10/27) of participants. Phenomizer identified the genes harbouring variants from HPO terms in 33% (9/27) of participants. This study shows the clinical efficacy that genetic testing has in the care of PID. However, it also highlights some of the disadvantages of gene panels in the rapidly moving field of PID genomics and current challenges in HPO term assignment for PID.

The physical environment in family childcare homes and children's physical activity.

BACKGROUND: Family childcare homes (FCCHs) are the second largest provider of childcare in the United States, yet little is known about how this setting influences children's physical activity, particularly related to the physical environment. Thus, the purpose of this study was to determine what aspects of the FCCH physical environment facilitate or hinder children's physical activity. METHODS: Data were collected from 166 FCCH providers and 496 preschool-aged children in 2013-2014 as part of the Keys to Healthy FCCHs study. Children's moderate-to-vigorous physical activity (MVPA) was measured using Actigraph GT3X+ accelerometers. Wear data from the childcare day were isolated, and cut-points were applied in order to calculate children's minutes of MVPA per hour. FCCH-level estimates of child MVPA per hour were calculated. Indoor and outdoor physical environment characteristics were assessed during a 2-day observation using the Environment and Policy Assessment and Observation modified for FCCHs. General linear models were used to examine the relationship between indoor, portable play equipment, and outdoor FCCH physical environment characteristics and children's MVPA per hour. RESULTS: Only indoor play space was significantly associated with children's MVPA (ß = 0.33; p = .034), indicating that when provided with more indoor space for active play, children were more physically active. No significant associations were noted between portable play equipment or the outdoor environment and children's MVPA. CONCLUSIONS: Indoor space was the only physical environment characteristic associated with children's MVPA, suggesting that teaching FCCH providers how to best utilize their indoor play space for active play may be a way to promote children's physical activity. Futures studies should explore the impact of other environmental characteristics of the FCCH (e.g., provider practices and policies) on children's physical activity.

The dynamics of benzene on Cu(111): a combined helium spin echo and dispersion-corrected DFT study into the diffusion of physisorbed aromatics on metal surfaces.

We use helium spin-echo spectroscopy (HeSE) to investigate the dynamics of the diffusion of benzene adsorbed on Cu(111). The results of these measurements show that benzene moves on the surface through an activated jump-diffusion process between the adsorption sites on a Bravais lattice. Density Functional Theory (DFT) calculations with van der Waals (vdW) corrections help us understand that the molecule diffuses by jumping through non-degenerate hollow sites. The results of the calculations shed light on the nature of the binding interaction between this prototypical aromatic molecule and the metallic surface. The highly accurate HeSE experimental data provide a quantitatively stringent benchmark for the vdW correction schemes applied to the DFT calculations and we compare the performances of several dispersion interaction schemes.

Two-axis control of a singlet-triplet qubit with an integrated micromagnet.

The qubit is the fundamental building block of a quantum computer. We fabricate a qubit in a silicon double-quantum dot with an integrated micromagnet in which the qubit basis states are the singlet state and the spin-zero triplet state of two electrons. Because of the micromagnet, the magnetic field difference ΔB between the two sides of the double dot is large enough to enable the achievement of coherent rotation of the qubit's Bloch vector around two different axes of the Bloch sphere. By measuring the decay of the quantum oscillations, the inhomogeneous spin coherence time T2* is determined. By measuring T2* at many different values of the exchange coupling J and at two different values of ΔB, we provide evidence that the micromagnet does not limit decoherence, with the dominant limits on T2* arising from charge noise and from coupling to nuclear spins.

The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure.

The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Cre-positive (SM22α)CaSR(Δflox/Δflox) [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca(2+)) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-l-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca(2+) concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.

Preventing childhood obesity in early care and education settings: lessons from two intervention studies.

BACKGROUND: Obesity prevention in young children is a public health priority. In the USA, nearly 10% of children less than 5 years of age are obese, and most attend some form of out-of-home child care. While a number of interventions have been conducted in early care and education settings, few have targeted the youngest children in care or the less formal types of child care like family child care homes. Additionally, only two previous studies provided recommendations to help inform future interventions. METHODS: This paper presents lessons learned from two distinct intervention studies in early care and education settings to help guide researchers and public health professionals interested in implementing and evaluating similar interventions. We highlight two studies: one targeting children ages 4 to 24 months in child care centres and the other intervening in children 18 months to 4 years in family child care homes. We include lessons from our pilot studies and the ongoing larger trials. RESULTS: To date, our experiences suggest that an intervention should have a firm basis in behaviour change theory; an advisory group should help evaluate intervention materials and plan for delivery; and realistic recruitment goals should recognize economic challenges of the business of child care. A flexible data collection approach and realistic sample size calculations are needed because of high rates of child (and sometimes facility) turnover. An intervention that is relatively easy to implement is more likely to appeal to a wide variety of early care and education providers. CONCLUSIONS: Interventions to prevent obesity in early care and education have the potential to reach large numbers of children. It is important to consider the unique features and similarities of centres and family child care homes and take advantage of lessons learned from current studies in order to develop effective, evidence-based interventions.

Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM.

BACKGROUND: Better biomarkers must be found to develop clinically useful urine tests for bladder cancer. Proteomics can be used to identify the proteins released by cancer cell lines and generate candidate markers for developing such tests. METHODS: We used shotgun proteomics to identify proteins released into culture media by eight bladder cancer cell lines. These data were compared with protein expression data from the Human Protein Atlas. Epidermal growth factor receptor (EGFR) was identified as a candidate biomarker and measured by ELISA in urine from 60 noncancer control subjects and from 436 patients with bladder cancer and long-term clinical follow-up. RESULTS: Bladder cancer cell lines shed soluble EGFR ectodomain. Soluble EGFR is also detectable in urine and is highly elevated in some patients with high-grade bladder cancer. Urinary EGFR is an independent indicator of poor bladder cancer-specific survival with a hazard ratio of 2.89 (95% CI 1.81-4.62, P<0.001). In multivariable models including both urinary EGFR and EpCAM, both biomarkers are predictive of bladder cancer-specific survival and have prognostic value over and above that provided by standard clinical observations. CONCLUSIONS: Measuring urinary EGFR and EpCAM may represent a simple and useful approach for fast-tracking the investigation and treatment of patients with the most aggressive bladder cancers.