Spatial distribution and determinants of childhood vaccination refusal in the United States

Parental refusal and delay of childhood vaccination has increased in recent years in the United States. This phenomenon challenges maintenance of herd immunity and increases the risk of outbreaks of vaccine-preventable diseases. We examine US county-level vaccine refusal for patients under five years of age collected during the period 2012--2015 from an administrative healthcare dataset. We model these data with a Bayesian zero-inflated negative binomial regression model to capture social and political processes that are associated with vaccine refusal, as well as factors that affect our measurement of vaccine refusal.Our work highlights fine-scale socio-demographic characteristics associated with vaccine refusal nationally, finds that spatial clustering in refusal can be explained by such factors, and has the potential to aid in the development of targeted public health strategies for optimizing vaccine uptake

Dallas with balls: televized sport, soap opera and male and female pleasures

Two of the most popular of television genres, soap opera and sports coverage have been very much differentiated along gender lines in terms of their audiences. Soap opera has been regarded very much as a 'gynocentric' genre with a large female viewing audience while the audiences for television sport have been predominantly male. Gender differentiation between the genres has had implications for the popular image of each. Soap opera has been perceived as inferior; as mere fantasy and escapism for women while television sports has been perceived as a legitimate, even edifying experience for men. In this article the authors challenge the view that soap opera and television sport are radically different and argue that they are, in fact, very similar in a number of significant ways. They suggest that both genres invoke similar structures of feeling and sensibility in their respective audiences and that television sport is a 'male soap opera'. They consider the ways in which the viewing context of each genre is related to domestic life and leisure, the ways in which the textual structure and conventions of each genre invoke emotional identification, and finally, the ways in which both genres re-affirm gender identities

An automated fitting procedure and software for dose-response curves with multiphasic features.

In cancer pharmacology (and many other areas), most dose-response curves are satisfactorily described by a classical Hill equation (i.e. 4 parameters logistical). Nevertheless, there are instances where the marked presence of more than one point of inflection, or the presence of combined agonist and antagonist effects, prevents straight-forward modelling of the data via a standard Hill equation. Here we propose a modified model and automated fitting procedure to describe dose-response curves with multiphasic features. The resulting general model enables interpreting each phase of the dose-response as an independent dose-dependent process. We developed an algorithm which automatically generates and ranks dose-response models with varying degrees of multiphasic features. The algorithm was implemented in new freely available Dr Fit software (sourceforge.net/projects/drfit/). We show how our approach is successful in describing dose-response curves with multiphasic features. Additionally, we analysed a large cancer cell viability screen involving 11650 dose-response curves. Based on our algorithm, we found that 28% of cases were better described by a multiphasic model than by the Hill model. We thus provide a robust approach to fit dose-response curves with various degrees of complexity, which, together with the provided software implementation, should enable a wide audience to easily process their own data.This work was funded by Cancer Research UK grant C14303/A17197.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/srep1470

Modelling of the cancer cell cycle as a tool for rational drug development: A systems pharmacology approach to cyclotherapy

The dynamic of cancer is intimately linked to a dysregulation of the cell cycle and signalling pathways. It has been argued that selectivity of treatments could exploit loss of checkpoint function in cancer cells, a concept termed "cyclotherapy". Quantitative approaches that describe these dysregulations can provide guidance in the design of novel or existing cancer therapies. We describe and illustrate this strategy via a mathematical model of the cell cycle that includes descriptions of the G1-S checkpoint and the spindle assembly checkpoint (SAC), the EGF signalling pathway and apoptosis. We incorporated sites of action of four drugs (palbociclib, gemcitabine, paclitaxel and actinomycin D) to illustrate potential applications of this approach. We show how drug effects on multiple cell populations can be simulated, facilitating simultaneous prediction of effects on normal and transformed cells. The consequences of aberrant signalling pathways or of altered expression of pro- or anti-apoptotic proteins can thus be compared. We suggest that this approach, particularly if used in conjunction with pharmacokinetic modelling, could be used to predict effects of specific oncogene expression patterns on drug response. The strategy could be used to search for synthetic lethality and optimise combination protocol designs

Interaction between Intrathecal Gabapentin and Adenosine in the Formalin Test of Rats

Spinal gabapentin and adenosine have been known to display an antinociceptive effect. We evaluated the nature of the interaction between gabapentin and adenosine in formalin-induced nociception at the spinal level. Male Sprague-Dawley rats were prepared for intrathecal catheterization. Pain was evoked by injection of formalin solution (5%, 50 µL) into the hindpaw. After examination of the effects of gabapentin and adenosine, the resulting interaction was investigated with isobolographic and fractional analyses. Neither gabapentin nor adenosine affected motor function. Gabapentin or adenosine decreased the sum of the number of flinches during phase 2, but not during phase 1 in the formalin test. Isobolographic analysis, in phase 2, revealed an additive interaction between gabapentin and adenosine. Taken together, intrathecal gabapentin and adenosine attenuated the facilitated state and interacted additively with each other

Characterisation of the substrate specificity of the nitrile hydrolyzing system of the acidotolerant black yeast Exophiala oligosperma R1

The `black yeast' Exophiala oligosperma R1 can utilise various organic nitriles under acidic conditions as nitrogen sources. The induction of a phenylacetonitrile converting activity was optimised by growing the strain in the presence of different nitriles and /or complex or inorganic nitrogen sources. The highest nitrile hydrolysing activity was observed with cells grown with 2-cyanopyridine and NaNO3. The cells metabolised the inducer and grew with 2-cyanopyridine as sole source of nitrogen. Cell extracts converted various (substituted) benzonitriles and phenylacetonitriles. They usually converted the isomers carrying a substituent in the meta-position with higher relative activities than the corresponding para- or ortho-substituted isomers. Aliphatic substrates such as acrylonitrile and 2-hydroxy-3-butenenitrile were also hydrolysed. The highest specific activity was detected with 4-cyanopyridine. Most nitriles were almost exclusively converted to the corresponding acids and no or only low amounts of the corresponding amides were formed. The cells hydrolysed amides only with extremely low activities. It was therefore concluded that the cells harboured a nitrilase activity. The specific activities of whole cells and cell extracts were compared for different nitriles and evidence obtained for limitation in the substrate-uptake by whole cells. The conversion of 2-hydroxy-3-butenenitrile to 2-hydroxy-3-butenoic acid at pH 4 demonstrated the unique ability of cells of E. oligosperma R1 to hydrolyse aliphatic α-hydroxynitriles under acidic conditions. The organism could grow with phenylacetonitrile as sole source of carbon, energy and nitrogen. The degradation of phenylacetonitrile presumably proceeds via phenylacetic acid, 2-hydroxyphenylacetic acid, 2,5-dihydroxyphenylacetic acid (homogentisate), maleylacetoacetate and fumarylacetoacetate

Hepatic Radiofrequency Ablation Using Multiple Probes: Ex Vivo and In Vivo Comparative Studies of Monopolar versus Multipolar Modes

OBJECTIVE: We wanted to compare the efficiency of multipolar radiofrequency ablation (RFA) using three perfused-cooled electrodes with multiple overlapping and simultaneous monopolar techniques for creating an ablation zone in ex vivo bovine livers and in in vivo porcine livers. MATERIALS AND METHODS: In the ex vivo experiments, we used a 200 W generator (Valleylab, CC-3 model) and three perfused-cooled electrodes or internally cooled electrodes to create 30 coagulation zones by performing consecutive monopolar RFA (group A, n = 10), simultaneous monopolar RFA (group B, n = 10) or multipolar RFA (group C, n = 10) in explanted bovine livers. In the consecutive mode, three ablation spheres were created by sequentially applying 150 watts radiofrequency (RF) energy to the internally cooled electrodes for 12 minutes each for a total of 36 minutes. In the simultaneous monopolar and multipolar modes, RF energy was concurrently applied to the three perfused-cooled electrodes for 20 minutes at 150 watt with instillation of 6% hypertonic saline at 2 mL/min. During RFA, we measured the temperatures of the treated area at its center. The changes in impedance, the current and liver temperature during RFA, as well as the dimensions of the thermal ablation zones, were compared among the three groups. In the in vivo experiments, three coagulations were created by performing multipolar RFA in a pig via laparotomy with using same parameter as the ex vivo study. RESULTS: In the ex vivo experiments, the impedance was gradually decreased during the RFA in groups B and C, but in group A, the impedance was increased during RFA and this induced activation by the pulsed RF technique. In groups A, B and C, the mean final-temperature values were 80+/-10 degrees C, 69+/-18 degrees C and 79+/-12 degrees C, respectively (p < 0.05). The multipolar mode created a larger volume of ablation than did the other modes: 37.6+/-4.0 cm3 (group A); 44.9+/-12.7 cm3 (group B); and 78.9+/-6.9 cm3 (group C) (p < 0.05). In the in vivo experiment, the pig well tolerated the RFA procedure and no major complications occurred during the 4 days of the follow-up period. The mean volume of coagulations produced by multipolar RFA in the pig liver was 60.5+/-17.9 cm3. CONCLUSION: For the multiple probe RFA, the multipolar mode with hypertonic saline instillation was more efficient in generating larger areas of thermal ablation than either the consecutive or simultaneous monopolar modes.ope