Development of the stria vascularis and potassium regulation in the human fetal cochlea : insights into hereditary sensorineural hearing loss

Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9–W18) and show the cochlear expression dynamics of key potassium‐regulating proteins. At W12, MITF+/SOX10+/KIT+ neural‐crest‐derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na(+)/K(+)‐ATPase‐positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1219–1240, 201

Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma

BACKGROUND: Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent METHODS: Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on RESULTS: A total of 29 new and 60 recurrent CONCLUSIONS: Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS fo

Linking the hydrodynamic and kinetic description of a dissipative relativistic conformal theory

We use the entropy production variational method to associate a one particle distribution function to the assumed known energy-momentum and entropy currents describing a relativistic conformal fluid. Assuming a simple form for the collision operator we find this one particle distribution function explicitly, and show that this method of linking the hydro and kinetic description is a non trivial generalization of Grad's ansatz. The resulting constitutive relations are the same as in the conformal dissipative type theories discussed in J. Peralta-Ramos and E. Calzetta, Phys. Rev. D {\bfseries 80}, 126002 (2009). Our results may prove useful in the description of freeze-out in ultrarelativistic heavy-ion collisions.Comment: v2: 23 pages, no figures, accepted in Phys. Rev.

Variation in use of targeted therapies for metastatic renal cell carcinoma

__Background:__ For patients with metastatic renal cell carcinoma (mRCC), targeted therapies have entered the market since 2006. The aims of this study were to evaluate the uptake and use of targeted therapies for mRCC in The Netherlands, examine factors associated with the prescription of targeted therapies in daily clinical practice and study their effectiveness in terms of overall survival (OS). __Methods:__ Two cohorts from PERCEPTION, a population-based registry of mRCC patients, were used: a 2008-2010 Cohort (n = 645) and a 2011-2013 Cohort (n = 233). Chi-squared tests for trend were used to study time trends in the use of targeted therapy. Patients were grouped based on the eligibility criteria of the SUTENT trial, the trial that led to sunitinib becoming standard of care, to investigate the use of targeted therapies amongst patients fulfilling those criteria. Multi-level logistic regression was used to identify patient subgroups that are less likely to receive targeted therapies. __Results:__ Approximately one-third of patients fulfilling SUTENT trial eligibility criteria did not receive any targeted therapy (29 % in the 2008-2010 Cohort; 35 % in the 2011-2013 Cohort). Patients aged 65+ years were less likely to receive targeted therapy in both cohorts and different risk groups (odds ratios range between 0.84-0.92); other factors like number of metastatic sites were of influence in some subgroups. Amongst treated patients, there was a decreasing trend in sunitinib use over time (p = 0.0061), and an increasing trend in pazopanib use (p = 0.0005). __Conclusions:__ Targeted therapies have largely replaced interferon-alfa as first-line standard of care. Nevertheless, many eligible patients in Dutch daily practice did not receive targeted therapies despite their ability to improve survival. Reasons for their apparent underutilisation should be examined more carefully

Bayesian Nonparametric Common Atoms Regression for Generating Synthetic Controls in Clinical Trials

The availability of electronic health records (EHR) has opened opportunities to supplement increasingly expensive and difficult to carry out randomized controlled trials (RCT) with evidence from readily available real world data. In this paper, we use EHR data to construct synthetic control arms for treatment-only single arm trials. We propose a novel nonparametric Bayesian common atoms mixture model that allows us to find equivalent population strata in the EHR and the treatment arm and then resample the EHR data to create equivalent patient populations under both the single arm trial and the resampled EHR. Resampling is implemented via a density-free importance sampling scheme. Using the synthetic control arm, inference for the treatment effect can then be carried out using any method available for RCTs. Alternatively the proposed nonparametric Bayesian model allows straightforward model-based inference. In simulation experiments, the proposed method vastly outperforms alternative methods. We apply the method to supplement single arm treatment-only glioblastoma studies with a synthetic control arm based on historical trials

Variability and reproducibility of flow-mediated dilatation in a multicentre clinical trial

Aims The aim of this study was to assess the reproducibility of flow-mediated dilatation (FMD) in a multicentre setting. Methods and results This study was performed as part of the dal-VESSEL trial in which FMD was measured in 19 vascular imaging centres in six European countries. A subgroup of patients who were allocated in the placebo group and scanned twice at each trial time point (substudy) was analysed. Intra-sonographer variability was calculated from FMD measurements 48 h apart. Centre variability and short-, medium-, and long-term reproducibility of FMD were calculated at 48 h and at 3 and 9 months intervals, respectively. Intra- and inter-reader variability was assessed by re-analysing the FMD images by three certified readers at two time intervals, 7 days apart. Sixty-seven patients were included. Variability between centres was comparable at 48 h and 3 months interval but almost doubled at 9 months. The mean absolute difference in %FMD was 1.04, 0.99, and 1.45% at the three time intervals, respectively. Curves were generated to indicate the number of patients required for adequate power in crossover and parallel study designs. Conclusion This study demonstrates for the first time that in a multicentre setting reproducible FMD measurements can be achieved for short- and medium-term evaluation, which are comparable with those reported from specialized laboratories. These findings justify the use of FMD as an outcome measure for short- and medium-term assessment of pharmacological intervention

Supersymmetry and the Lorentz Fine Tuning Problem

If physics at the Planck scale requires new conceptions of space-time, then generic renormalizable field theories predict observable violations of Lorentz invariance in the low energy sector. The little recognized ``Lorentz Fine Tuning Problem'' comes from logarithmic loop corrections which are not suppressed to the enormous extent commonly assumed. Fine-tuning of parameters at the Planck scale is one possible but unpalatable solution. Here we show that violation of Lorentz invariance is highly suppressed in a supersymmetric theory, the Wess-Zumino model. We conjecture that supersymmetry may be further motivated by yet another fine tuning problem of ordinary quantum field theories.Comment: 9 pages, 1 figur