Clinical Influences in the Multidisciplinary Management of Small Renal Masses at a Tertiary Referral Center

Introduction We designed a multidisciplinary Small Renal Mass Center to help patients decide among treatment options and individualize therapy for small renal masses. In this model physicians and support staff from multiple specialties work as a team to evaluate and devise a treatment plan for patients at the same organized visit. Methods We retrospectively reviewed the records of 263 patients seen from 2009 to 2014. Monitored patient characteristics included age, Charlson comorbidity index, body mass index, nephrometry score, tumor size and estimated glomerular filtration rate. Univariate and multivariate analyses were performed to identify patient characteristics associated with each treatment choice. Results Of the cohort 88 patients elected active surveillance, 64 underwent ablation and 111 were treated with surgery, including partial and radical nephrectomy in 74 and 37, respectively. There were significant associations between treatment modality and age, Charlson comorbidity index, tumor size and estimated glomerular filtration rate. Mean patient age at presentation was 61.1 years. Patients with a high Charlson comorbidity index score (greater than 5) or a decreased estimated glomerular filtration rate (less than 60 ml/minute/1.73 m2) were more likely to undergo active surveillance (41.6% and 35%) and ablative therapy (29.6% and 34%) vs partial nephrectomy (10.6% and 9%, respectively, each p \u3c0.001). On multivariable analysis age, tumor size and estimated glomerular filtration rate remained significantly associated with modality after adjustment for all other factors (each p \u3c0.001). Conclusions The Small Renal Mass Center enables patients to assess the various treatment modalities for a small renal mass in a single setting. By providing simultaneous access to the various specialists it provides an invaluable opportunity for informed patient decision making. © 2016 American Urological Association Education and Research, Inc

Development of functional connectivity during adolescence:A longitudinal study using an action-observation paradigm

Successful interpersonal interactions rely on an ability to read the emotional states of others and to modulate one's own behavior in response. The actions of others serve as valuable social stimuli in this respect, offering the observer an insight into the actor's emotional state. Social cognition continues to mature throughout adolescence. Here we assess longitudinally the development of functional connectivity during early adolescence within two neural networks implicated in social cognition: one network of brain regions consistently engaged during action observation and another one associated with mentalizing. Using fMRI, we reveal a greater recruitment of the social-emotional network during the observation of angry hand actions in male relative to female adolescents. These findings are discussed in terms of known sex differences in adolescent social behavior

Evolutionary bi-stability in pathogen transmission mode

Many pathogens transmit to new hosts by both infection (horizontal transmission) and transfer to the infected host's offspring (vertical transmission). These two transmission modes require speci®c adap- tations of the pathogen that can be mutually exclusive, resulting in a trade-off between horizontal and vertical transmission. We show that in mathematical models such trade-offs can lead to the simultaneous existence of two evolutionary stable states (evolutionary bi-stability) of allocation of resources to the two modes of transmission. We also show that jumping between evolutionary stable states can be induced by gradual environmental changes. Using quantitative PCR-based estimates of abundance in seed and vege- tative parts, we show that the pathogen of wheat, Phaeosphaeria nodorum, has jumped between two distinct states of transmission mode twice in the past 160 years, which, based on published evidence, we interpret as adaptation to environmental change. The ®nding of evolutionary bi-stability has impli- cations for human, animal and other plant diseases. An ill-judged change in a disease control programme could cause the pathogen to evolve a new, and possibly more damaging, combination of transmission modes. Similarly, environmental changes can shift the balance between transmission modes, with adverse effects on human, animal and plant health

New Constraints on the Complex Mass Substructure in Abell 1689 from Gravitational Flexion

In a recent publication, the flexion aperture mass statistic was found to provide a robust and effective method by which substructure in galaxy clusters might be mapped. Moreover, we suggested that the masses and mass profile of structures might be constrained using this method. In this paper, we apply the flexion aperture mass technique to HST ACS images of Abell 1689. We demonstrate that the flexion aperture mass statistic is sensitive to small-scale structures in the central region of the cluster. While the central potential is not constrained by our method, due largely to missing data in the central 0.5$^\prime$ of the cluster, we are able to place constraints on the masses and mass profiles of prominent substructures. We identify 4 separate mass peaks, and use the peak aperture mass signal and zero signal radius in each case to constrain the masses and mass profiles of these substructures. The three most massive peaks exhibit complex small-scale structure, and the masses indicated by the flexion aperture mass statistic suggest that these three peaks represent the dominant substructure component of the cluster ($\sim 7\times 10^{14}h^{-1}M_\odot$). Their complex structure indicates that the cluster -- far from being relaxed -- may have recently undergone a merger. The smaller, subsidiary peak is located coincident with a group of galaxies within the cluster, with mass $\sim 1\times10^{14}h^{-1}M_\odot$. These results are in excellent agreement with previous substructure studies of this cluster.Comment: 18 pages, 10 figures, MNRAS accepted (7 Dec 2010

An MCMC Fitting Method for Triaxial Dark Matter Haloes

Measuring the 3D distribution of mass on galaxy cluster scales is a crucial test of the LCDM model, providing constraints on the behaviour of dark matter. Recent work investigating mass distributions of individual galaxy clusters (e.g. Abell 1689) using weak and strong gravitational lensing has revealed potential inconsistencies between the predictions of structure formation models relating halo mass to concentration and those relationships as measured in massive clusters. However, such analyses employ simple spherical halo models while a growing body of work indicates that triaxial 3D halo structure is both common and important in parameter estimates. The very strong assumptions about the symmetry of the lensing halo implied with circular or perturbative elliptical NFW models are not physically motivated and lead to incorrect parameter estimates with significantly underestimated error bars. We here introduce a Markov Chain Monte Carlo (MCMC) method to fit fully triaxial models to weak lensing data that gives parameter and error estimates that fully incorporate the true uncertainty present in nature. Applying the MCMC triaxial fitting method to a population of NFW triaxial lenses drawn from the shape distribution of structure formation simulations, we find that including triaxiality cannot explain a population of massive, highly concentrated clusters within the framework of LCDM, but easily explains rare cases of apparently massive, highly concentrated, very efficient lensing clusters. Our MCMC triaxial NFW fitting method is easily expandable to include constraints from additional data types, and its application returns model parameters and errors that more accurately capture the true (and limited) extent of our knowledge of the structure of galaxy cluster lenses. (abridged)Comment: 18 pages, 15 figures. Updated to match published versio

Pretransplant assessment of human liver grafts by plasma lecithin: cholesterol acyltransferase (LCAT) activity in multiple organ donors.

In spite of the improved outcome of orthotopic liver transplantation (OLTx), primary graft nonfunction remains one of the life-threatening problems following OLTx. The purpose of this study was to evaluate plasma lecithin: cholesterol acyltransferase (LCAT) activity in multiple organ donors as a predictor of liver allograft viability prior to OLTx. Thirty-nine donors were studied during a 5-month period between April and August 1988. Allograft hepatectomy was performed using a rapid technique or its minor modification with hilar dissections, and the allografts were stored cold (4 degrees C) in University of Wisconsin (UW) solution. Early post-transplant allograft function was classified as good, fair, or poor, according to the highest SGOT, SGPT, and prothrombin time within 5 days following OLTx. Procurement records were reviewed to identify donor data, which included conventional liver function tests, duration of hospital stay, history of cardiac arrest, and graft ischemic time. Blood samples from the donors were drawn immediately prior to aortic crossclamp, and from these plasma LCAT activity was determined. Plasma LCAT activity of all donors was significantly lower than that of healthy controls (12.4 +/- 8.0 vs 39.2 +/- 13.3 micrograms/ml per hour, P less than 0.01). LCAT activity (16.4 +/- 8.3 micrograms/ml per hour) in donors of grafts with good function was significantly higher than that in those with fair (8.6 +/- 4.5 micrograms/ml per hour, P less than 0.01) or poor (7.3 +/- 2.4 micrograms/ml per hour, P less than 0.01) function.(ABSTRACT TRUNCATED AT 250 WORDS

The Burst and Transient Source Experiment (BATSE) Earth Occultation Catalog of Low-Energy Gamma-Ray Sources

The Burst and Transient Source Experiment (BATSE), aboard the Compton Gamma Ray Observatory (CGRO), provided a record of the low-energy gamma-ray sky (20-1000 keV) between 1991 April and 2000 May (9.1y). Using the Earth Occultation Technique to extract flux information, a catalog of sources using data from the BATSE large area detectors has been prepared. The first part of the catalog consists of results from the monitoring of 58 sources, mostly Galactic. For these sources, we have included tables of flux and spectral data, and outburst times for transients. Light curves (or flux histories) have been placed on the world wide web. We then performed a deep-sampling of 179 objects (including the aforementioned 58 objects) combining data from the entire 9.1y BATSE dataset. Source types considered were primarily accreting binaries, but a small number of representative active galaxies, X-ray-emitting stars, and supernova remnants were also included. The deep sample results include definite detections of 83 objects and possible detections of 36 additional objects. The definite detections spanned three classes of sources: accreting black hole and neutron star binaries, active galaxies and supernova remnants. Flux data for the deep sample are presented in four energy bands: 20-40, 40-70, 70-160, and 160-430 keV. The limiting average flux level (9.1 y) for the sample varies from 3.5 to 20 mCrab (5 sigma) between 20 and 430 keV, depending on systematic error, which in turn is primarily dependent on the sky location. To strengthen the credibility of detection of weaker sources (5-25 mCrab), we generated Earth occultation images, searched for periodic behavior using FFT and epoch folding methods, and critically evaluated the energy-dependent emission in the four flux bands.Comment: 64 pages, 17 figures, abstract abridged, Accepted by ApJ

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis

Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials

Background: Funding and resources for low prevalent neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) are limited, and optimising their use is vital for efficient drug development. In this study, we review the design assumptions for pivotal ALS clinical trials with time-to-event endpoints and provide optimised settings for future trials. Methods: We extracted design settings from 13 completed placebo-controlled trials. Optimal assumptions were estimated using parametric survival models in individual participant data (n=4991). Designs were compared in terms of sample size, trial duration, drug use and costs. Results: Previous trials overestimated the hazard rate by 18.9% (95% CI 3.4% to 34.5%, p=0.021). The median expected HR was 0.56 (range 0.33–0.66). Additionally, we found evidence for an increasing mean hazard rate over time (Weibull shape parameter of 2.03, 95% CI 1.93 to 2.15, p<0.001), which affects the design and planning of future clinical trials. Incorporating accrual time and assuming an increasing hazard rate at the design stage reduced sample size by 33.2% (95% CI 27.9 to 39.4), trial duration by 17.4% (95% CI 11.6 to 23.3), drug use by 14.3% (95% CI 9.6 to 19.0) and follow-up costs by 21.2% (95% CI 15.6 to 26.8). Conclusions: Implementing distributional knowledge and incorporating accrual at the design stage could achieve large gains in the efficiency of ALS clinical trials with time-to-event endpoints. We provide an open-source platform that helps investigators to make more accurate sample size calculations and optimise the use of their available resources

A New Look at Massive Clusters: weak lensing constraints on the triaxial dark matter halos of Abell 1689, Abell 1835, & Abell 2204

Measuring the 3D distribution of mass on galaxy cluster scales is a crucial test of the LCDM model, providing constraints on the nature of dark matter. Recent work investigating mass distributions of individual galaxy clusters (e.g. Abell 1689) using weak and strong gravitational lensing has revealed potential inconsistencies between the predictions of structure formation models relating halo mass to concentration and those relationships as measured in massive clusters. However, such analyses employ simple spherical halo models while a growing body of work indicates that triaxial 3D halo structure is both common and important in parameter estimates. We recently introduced a Markov Chain Monte Carlo (MCMC) method to fit fully triaxial models to weak lensing data that gives parameter and error estimates that fully incorporate the true shape uncertainty present in nature. In this paper we apply that method to weak lensing data obtained with the ESO/MPG Wide-Field Imager for galaxy clusters A1689, A1835, and A2204, under a range of Bayesian priors derived from theory and from independent X-ray and strong lensing observations. For Abell 1689, using a simple strong lensing prior we find marginalized mean parameter values M_200 = (0.83 +- 0.16)x10^15 M_solar/h and C=12.2 +- 6.7, which are marginally consistent with the mass-concentration relation predicted in LCDM. The large error contours that accompany our triaxial parameter estimates more accurately represent the true extent of our limited knowledge of the structure of galaxy cluster lenses, and make clear the importance of combining many constraints from other theoretical, lensing (strong, flexion), or other observational (X-ray, SZ, dynamical) data to confidently measure cluster mass profiles. (Abridged)Comment: 21 pages, 10 figures, accepted for publication in MNRA