Why Be One Protein When You Can Affect Many? The Multiple Roles of YB-1 in Lung Cancer and Mesothelioma.
Lung cancers and malignant pleural mesothelioma (MPM) have some of the worst 5-year survival rates of all cancer types, primarily due to a lack of effective treatment options for most patients. Targeted therapies have shown some promise in thoracic cancers, although efficacy is limited only to patients harboring specific mutations or target expression. Although a number of actionable mutations have now been identified, a large population of thoracic cancer patients have no therapeutic options outside of first-line chemotherapy. It is therefore crucial to identify alternative targets that might lead to the development of new ways of treating patients diagnosed with these diseases. The multifunctional oncoprotein Y-box binding protein-1 (YB-1) could serve as one such target. Recent studies also link this protein to many inherent behaviors of thoracic cancer cells such as proliferation, invasion, metastasis and involvement in cancer stem-like cells. Here, we review the regulation of YB-1 at the transcriptional, translational, post-translational and sub-cellular levels in thoracic cancer and discuss its potential use as a biomarker and therapeutic target.


Perceived oral health status and unmet dental needs among adults in Union County.
This study assessed the dental attitudes and perceived dental needs of adult residents of Union County. The area is a unique model of dental-health provider deficiencies in the United States--Union County is completely non-fluoridated, lacks public oral health services and does not have full-time licensed dentists within the county. Study participants included 513 adults who completed a 22-item multiple-choice survey questionnaire administered at the county's major supermarket. Among the survey participants, 48 percent rated the condition of their teeth as fair or poor. Forty-one participants reported having a dental problem in the past 12 months, and but did not see a dentist. Union County's lack of fluoridated community water, its high prevalence of cigarette smoking (29.3 percent, 11th highest among Florida's 67 counties), high levels of poverty and lack of access to dental care indicates county residents are a high risk for oral disease. A comprehensive dental public approach is needed to improve oral health in that county.


Opinions about electronic cigarette use in smoke-free areas among U.S. Adults, 2012.
In the United States, electronic cigarettes (e-cigarettes) are currently unregulated, extensively marketed, and experiencing a rapid increase in use. The purpose of this study was to examine the opinions of U.S. adults about e-cigarette use in smoke-free public areas. Data were obtained from the online HealthStyle survey administered to a probability sample of a nationally representative online panel. The study included 4,043U.S. adults, aged 18 years or older who responded to this question, "Do you think e-cigarette should be allowed to be used in public areas where tobacco smoking is prohibited?" Multinomial logistic regression analyses were used to examine opinions on e-cigarette use in smoke-free areas by sex, age, race/ethnicity, household income, education, census region, and cigarette smoking status and e-cigarette awareness and ever use. Overall, about 40% of adults were uncertain whether e-cigarettes should be allowed in smoke-free areas, 37% opposed, while 23% favored their use in smoke-free public places. Multinomial logistic regression analyses showed that adults who were aware, ever used e-cigarettes, and current cigarette smokers were more likely to express an "in favor" opinion than adults who expressed an uncertain opinion (don't know). Over 75% of U.S. adults reported uncertainty or disapproval of the use of e-cigarettes in smoke-free areas. Current cigarette smokers, adults aware or have ever used e-cigarettes were more supportive to exempting e-cigarettes from smoking restrictions. With impending regulation and the changing e-cigarette landscape, continued monitoring and research on public opinions about e-cigarette use in smoke-free places are needed.


Tomato transcriptome and mutant analyses suggest a role for plant stress hormones in the interaction between fruit and Botrytis cinerea.
Fruit-pathogen interactions are a valuable biological system to study the role of plant development in the transition from resistance to susceptibility. In general, unripe fruit are resistant to pathogen infection but become increasingly more susceptible as they ripen. During ripening, fruit undergo significant physiological and biochemical changes that are coordinated by complex regulatory and hormonal signaling networks. The interplay between multiple plant stress hormones in the interaction between plant vegetative tissues and microbial pathogens has been documented extensively, but the relevance of these hormones during infections of fruit is unclear. In this work, we analyzed a transcriptome study of tomato fruit infected with Botrytis cinerea in order to profile the expression of genes for the biosynthesis, modification and signal transduction of ethylene (ET), salicylic acid (SA), jasmonic acid (JA), and abscisic acid (ABA), hormones that may be not only involved in ripening, but also in fruit interactions with pathogens. The changes in relative expression of key genes during infection and assays of susceptibility of fruit with impaired synthesis or perception of these hormones were used to formulate hypotheses regarding the involvement of these regulators in the outcome of the tomato fruit-B. cinerea interaction.


MicroRNA-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling.
Formation and remodeling of the vasculature during development and disease involve a highly conserved and precisely regulated network of attractants and repellants. Various signaling pathways control the behavior of endothelial cells, but their posttranscriptional dose titration by microRNAs is poorly understood. To identify microRNAs that regulate angiogenesis. We show that the highly conserved microRNA family encoding miR-10 regulates the behavior of endothelial cells during angiogenesis by positively titrating proangiogenic signaling. Knockdown of miR-10 led to premature truncation of intersegmental vessel growth in the trunk of zebrafish larvae, whereas overexpression of miR-10 promoted angiogenic behavior in zebrafish and cultured human umbilical venous endothelial cells. We found that miR-10 functions, in part, by directly regulating the level of fms-related tyrosine kinase 1 (FLT1), a cell-surface protein that sequesters vascular endothelial growth factor, and its soluble splice variant sFLT1. The increase in FLT1/sFLT1 protein levels upon miR-10 knockdown in zebrafish and in human umbilical venous endothelial cells inhibited the angiogenic behavior of endothelial cells largely by antagonizing vascular endothelial growth factor receptor 2 signaling. Our study provides insights into how FLT1 and vascular endothelial growth factor receptor 2 signaling is titrated in a microRNA-mediated manner and establishes miR-10 as a potential new target for the selective modulation of angiogenesis.


Should General Practitioners Issue a Sick Certificate to Employees Who Consult for Low Back Pain in Primary Care?
Back pain is a common problem and has significant societal impact. Sickness certification is commonly issued to patients consulting their general practitioner with low back pain. The aim of this study was to investigate the association of certification for low back pain with clinical outcomes and cost consequences. A prospective cohort study using linked questionnaire and medical record data from 806 low back pain patients in 8 UK general practices: comparison of 116 (14.4%) who received a sickness certificate versus 690 who did not receive certification. The primary clinical measure was the Roland and Morris Disability Questionnaire (RMDQ). Data on back pain consultation and work absenteeism were used to calculate healthcare and societal costs. Participants issued a sickness certificate had higher back-related disability at baseline consultation and 6-month follow-up [mean difference 3.1 (95% CI 1.8, 4.4) on the RMDQ], indicating worse health status. After fully adjusting for baseline differences, most changes in clinical outcomes at 6 months were not significantly different between study groups. Productivity losses were significantly higher for the certification group, with most absence occurring after the expected end of certification; mean difference in costs due to absenteeism over 6 months was £1,956 (95% CI £941, £3040). There was no clear evidence of a difference in clinical outcomes between individuals issued a sickness certificate and those not issued a certification for their back pain. With little overall contrast in clinical outcomes, policy makers and care providers may wish to draw on the likely difference in societal costs alongside issues in ethical and moral care in their consideration of patient care for low back pain.


Religious pro-sociality? Experimental evidence from a sample of 766 Spaniards.
This study explores the relationship between several personal religion-related variables and social behaviour, using three paradigmatic economic games: the dictator (DG), ultimatum (UG), and trust (TG) games. A large carefully designed sample of the urban adult population in Granada (Spain) is employed (N = 766). From participants' decisions in these games we obtain measures of altruism, bargaining behaviour and sense of fairness/equality, trust, and positive reciprocity. Three dimensions of religiosity are examined: (i) religious denomination; (ii) intensity of religiosity, measured by active participation at church services; and (iii) conversion out into a different denomination than the one raised in. The major results are: (i) individuals with "no religion" made decisions closer to rational selfish behaviour in the DG and the UG compared to those who affiliate with a "standard" religious denomination; (ii) among Catholics, intensity of religiosity is the key variable that affects social behaviour insofar as religiously-active individuals are generally more pro-social than non-active ones; and (iii) the religion raised in seems to have no effect on pro-sociality, beyond the effect of the current measures of religiosity. Importantly, behaviour in the TG is not predicted by any of the religion-related variables we analyse. While the results partially support the notion of religious pro-sociality, on the other hand, they also highlight the importance of closely examining the multidimensional nature of both religiosity and pro-social behaviour.


Generalized Molecular Descriptors Derived From Event-Based Discrete Derivative.
In the present study, a generalized approach for molecular structure characterization is introduced, based on the relation frequency matrix (F) representation of the molecular graph and the subsequent calculation of the corresponding discrete derivative (finite difference) over a pair of elements (atoms). In earlier publications (22- 24), an unique event, named connected subgraphs, (based on the Kier-Hall's subgraphs) was systematically employed for the computation of the matrix F. The present report is a generalization of this notion, in which eleven additional events are introduced, classified in three categories, namely, topological (terminal paths, vertex path incidence, quantum subgraphs, walks of length k, Sach's subgraphs), fingerprints (MACCs, E-state and substructure fingerprints) and atomic contributions (Ghose and Crippen atom-types for hydrophobicity and refractivity) for F generation. The events are intended to capture diverse information by the generation or search of different kinds of substructures from the graph representation of a molecule. The discrete derivative over duplex atom relations are calculated for each event, and the resulting derivatives, local vertex invariants (LOVIs) are finally obtained. These LOVIs are subsequently employed as the basis for the calculation of global and local indices over groups of atoms (heteroatoms, halogens, methyl carbons, etc.), by using norms, means, statistics and classical algorithms as aggregator (fusion) operators. These indices were implemented in our house software DIVATI (Derivative Type Indices, a new module of TOMOCOMDCARDD system). DIVATI provides a friendly and cross-platform graphical user interface, developed in the Java programming language and is freely available at: http: //www.tomocomd.com. Factor analysis shows that the presented events are rather orthogonal and collect diverse information about the chemical structure. Finally, QSPR models were built to describe the logP and logK of 34 furylethylenes derivatives using the eleven events. Generally, the equations obtained according to these events showed high correlations, with the Sach's sub-graphs and Multiplicity events showing the best behavior in the description of logK (Q2 LOO value of 99.06%) and logP (Q2 LOO value of 98.1 %), respectively. These results show that these new eventbased indices constitute a powerful approach for chemoinformatics studies.


Student retention practices in associate degree, entry-level dental hygiene programs.
The main purpose of this study was to investigate student retention strategies and practices implemented in associate degree, entry-level dental hygiene programs. Included are student attrition issues, academic standards, re-entry policies, and clinical remediation strategies. A survey consisting of forced choice and open-ended questions was mailed to 31 randomly selected associate degree, entry-level dental hygiene programs. Surveys were analyzed using descriptive statistics and frequency distributions. Open-ended questions were analyzed using the constant comparative qualitative method to identify recurring themes. There was an 80% (n=25) return response to the survey. The findings of this study determined that dental hygiene programs are graduating, on average, a higher percentage (83%) of students when compared to two-year, associate degree programs in general (46%). The primary reasons reported by respondents for student attrition included: academic difficulties (88%), dissatisfaction with career choice (76%), family/personal responsibilities (72%), and clinical skill difficulties (56%). A wide variety of retention strategies were reported. Those most often cited were academic remediation (92%), clinical skill development/remediation (84%), academic advising (84%), financial aid assistance (84%), and tutoring (80%). Participating programs also reported setting high academic and ethical standards. Specific criteria for student re-entry were discussed. The findings of this study suggest that associate degree, entry-level dental hygiene programs are committed to student retention and make considerable efforts to help students succeed. Student retention efforts could be enhanced for those student groups identified as possibly being at high risk for attrition. The findings and recommendations in this investigation may assist associate degree, entry-level dental hygiene programs in their efforts to retain a higher percentage of students.


Recurrence of suicidal ideation across depressive episodes.
In recent years it has become clear that depression is a recurrent disorder, with the risk of recurrence in those with two or more episodes being as high as 90%. This has prompted interest in the consistency of individual depressive symptoms across consecutive episodes, an issue that is important for symptoms such as suicidal ideation, where a past history may give important indicators of future behaviour. We prospectively examined 69 individuals with a history of Major Depression, over 12 months, 38 of whom experienced a recurrence of major depression during the follow-up period. Spearman's rank order correlations between severity ratings of each symptom of major depression during a previous episode and severity ratings at recurrence showed significant associations for suicidality, guilt or worthlessness and thinking difficulties only. Weighted kappa coefficients indicated relatively low levels of agreement across episodes for most diagnostic symptoms, with suicidality showing the strongest relationship. Using a broad definition of suicidality-- any reporting of thoughts of death or suicide during episode-- a much higher level of agreement (kappa = .64) was found, with 83% of individuals falling into the same category (suicidal/non-suicidal) at both episodes. This study was based on a relatively small sample and examines re-emergence of suicidal ideation in the absence of suicidal behaviour. This study provides preliminary evidence of cross-episode consistency in the recurrence of suicidal ideation, in line with the differential activation theory of suicidality in depression.


Assemblies of d-Peptides for Targeting Cell Nucleolus.
Selectively targeting the cell nucleolus remains a challenge. Here, we report the first case in which d-peptides form membraneless molecular condensates with RNA for targeting cell nucleolus. A d-peptide derivative, enriched with lysine and hydrophobic residues, self-assembles to form nanoparticles, which enter cells through clathrin-dependent endocytosis and mainly accumulate at the cell nucleolus. A structural analogue of the d-peptide reveals that the particle morphology of the assemblies, which depends on the side chain modification, favors the cellular uptake. In contrast to those of the d-peptide, the assemblies of the corresponding l-enantiomer largely localize in cell lysosomes. Preliminary mechanism study suggests that the d-peptide nanoparticles interact with RNA to form membraneless condensates in the nucleolus, which further induces DNA damage and results in cell death. This work illustrates a new strategy for rationally designing supramolecular assemblies of d-peptides for targeting subcellular organelles.


BEAGLE: an application programming interface and high-performance computing library for statistical phylogenetics.
Phylogenetic inference is fundamental to our understanding of most aspects of the origin and evolution of life, and in recent years, there has been a concentration of interest in statistical approaches such as Bayesian inference and maximum likelihood estimation. Yet, for large data sets and realistic or interesting models of evolution, these approaches remain computationally demanding. High-throughput sequencing can yield data for thousands of taxa, but scaling to such problems using serial computing often necessitates the use of nonstatistical or approximate approaches. The recent emergence of graphics processing units (GPUs) provides an opportunity to leverage their excellent floating-point computational performance to accelerate statistical phylogenetic inference. A specialized library for phylogenetic calculation would allow existing software packages to make more effective use of available computer hardware, including GPUs. Adoption of a common library would also make it easier for other emerging computing architectures, such as field programmable gate arrays, to be used in the future. We present BEAGLE, an application programming interface (API) and library for high-performance statistical phylogenetic inference. The API provides a uniform interface for performing phylogenetic likelihood calculations on a variety of compute hardware platforms. The library includes a set of efficient implementations and can currently exploit hardware including GPUs using NVIDIA CUDA, central processing units (CPUs) with Streaming SIMD Extensions and related processor supplementary instruction sets, and multicore CPUs via OpenMP. To demonstrate the advantages of a common API, we have incorporated the library into several popular phylogenetic software packages. The BEAGLE library is free open source software licensed under the Lesser GPL and available from http://beagle-lib.googlecode.com. An example client program is available as public domain software.


Metagenomic approaches in microbial ecology: an update on whole-genome and marker gene sequencing analyses.
Metagenomics and marker gene approaches, coupled with high-throughput sequencing technologies, have revolutionized the field of microbial ecology. Metagenomics is a culture-independent method that allows the identification and characterization of organisms from all kinds of samples. Whole-genome shotgun sequencing analyses the total DNA of a chosen sample to determine the presence of micro-organisms from all domains of life and their genomic content. Importantly, the whole-genome shotgun sequencing approach reveals the genomic diversity present, but can also give insights into the functional potential of the micro-organisms identified. The marker gene approach is based on the sequencing of a specific gene region. It allows one to describe the microbial composition based on the taxonomic groups present in the sample. It is frequently used to analyse the biodiversity of microbial ecosystems. Despite its importance, the analysis of metagenomic sequencing and marker gene data is quite a challenge. Here we review the primary workflows and software used for both approaches and discuss the current challenges in the field.


Bayesian sparse partial least squares.
Partial least squares (PLS) is a class of methods that makes use of a set of latent or unobserved variables to model the relation between (typically) two sets of input and output variables, respectively. Several flavors, depending on how the latent variables or components are computed, have been developed over the last years. In this letter, we propose a Bayesian formulation of PLS along with some extensions. In a nutshell, we provide sparsity at the input space level and an automatic estimation of the optimal number of latent components. We follow the variational approach to infer the parameter distributions. We have successfully tested the proposed methods on a synthetic data benchmark and on electrocorticogram data associated with several motor outputs in monkeys.


Japan's voluntary lockdown.
Japan's government has taken a number of measures, including declaring a state of emergency, to combat the spread COVID-19. We examine the mechanisms through which the government's policies have led to changes in people's behavior. Using smartphone location data, we construct a daily prefecture-level stay-at-home measure to identify the following two effects: (1) the effect that citizens refrained from going out in line with the government's request, and (2) the effect that government announcements reinforced awareness with regard to the seriousness of the pandemic and people voluntarily refrained from going out. Our main findings are as follows. First, the declaration of the state of emergency reduced the number of people leaving their homes by 8.5% through the first channel, which is of the same order of magnitude as the estimates obtained for lockdowns in the United States. Second, a 1% increase in new infections in a prefecture reduces people's outings in that prefecture by 0.027%. Third, the government's requests are responsible for about one quarter of the decrease in outings in Tokyo, while the remaining three quarters are the result of citizens obtaining new information through government announcements and the daily release of the number of infections. The findings suggest that what mattered for containing the spread of COVID-19 was not strong, legally binding measures but the provision of appropriate information that encouraged people to change their behavior.


Polyphenol Intake and Epithelial Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.
Despite some epidemiological evidence on the protective effects of polyphenol intake on epithelial ovarian cancer (EOC) risk from case-control studies, the evidence is scarce from prospective studies and non-existent for several polyphenol classes. Therefore, we aimed to investigate the associations between the intake of total, classes and subclasses of polyphenols and EOC risk in a large prospective study. The study was conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 309,129 adult women recruited mostly from the general population. Polyphenol intake was assessed through validated country-specific dietary questionnaires and the Phenol-Explorer database. During a mean follow-up of 14 years, 1469 first incident EOC cases (including 806 serous, 129 endometrioid, 102 mucinous, and 67 clear cell tumours) were identified. In multivariable-adjusted Cox regression models, the hazard ratio in the highest quartile of total polyphenol intake compared with the lowest quartile (HRQ4vsQ1) was 1.14 (95% CI 0.94-1.39; p-trend = 0.11). Similarly, the intake of most classes and subclasses of polyphenols were not related to either overall EOC risk or any EOC subtype. A borderline statistically significant positive association was observed between phenolic acid intake (HRQ4vsQ1 = 1.20, 95% CI 1.01-1.43; p-trend = 0.02) and EOC risk, especially for the serous subtype and in women with obesity, although these associations did not exceed the Bonferroni correction threshold. The current results do not support any association between polyphenol intake and EOC in our large European prospective study. Results regarding phenolic acid intake need further investigation.


Pulmonary vein isolation supported by MRI-derived 3D-augmented biplane fluoroscopy: a feasibility study and a quantitative analysis of the accuracy of the technique.
Despite the advancement of technology in electroanatomic mapping systems (EAMS), fluoroscopy remains a necessary, basic imaging modality for electrophysiology procedures. We present a feasibility study of new software that enables 3D-augmented fluoroscopy in biplane catheterization laboratories for planning and guidance of pulmonary vein isolation (PVI). The computer-assisted overlay registration accuracy was assessed in a clinical setting using an automatic calculation of overlay projection geometry that was derived from hardware sensors in C-arms, detectors, and patient table. Consecutive patients (n = 89) underwent left atrium (LA) magnetic resonance imaging MRI scan prior to PVI. Ideal ablation lines encircling the ipsilateral pulmonary veins (PVs) at antral level were drawn onto the segmented LA surface. The 3D-model was superimposed onto biplane fluoroscopy and matched with angiographies of LA and PVs. Three-dimensional-overlay projection geometry was automatically calculated from C-arm, detectors, and table sensors. Accuracy of technique was assessed as alignment of MRI-derived 3D overlay and angiographic LA/PV anatomy. Integrity of registered overlay was quantified using landmark measurements. Alignment offsets were 1.3 ± 1.5 mm in left PV, 1.2 ± 1.5 mm in right PV, and 1.1 ± 1.4 mm in LA roof region. Bravais-Pearson correlation of the landmark measurements was r = 0.978 (s < 0.01), mean offset between landmark distance measurements was 1.4 ± 0.78 mm. Average time needed for overlay registration was 9.5 ± 3.5 seconds. MRI-derived 3D-augmented fluoroscopy demonstrated a high level of accuracy when compared with LA/PV angiography. The new system could be especially useful to guide procedures not supported by EAMS, such as cryotechnique PVI.


Ethylene limits abscisic acid- or soil drying-induced stomatal closure in aged wheat leaves.
The mechanism of age-induced decreased stomatal sensitivity to abscisic acid (ABA) and soil drying has been explored here. Older, fully expanded leaves partly lost their ability to close stomata in response to foliar ABA sprays, and soil drying which stimulated endogenous ABA production, while young fully expanded leaves closed their stomata more fully. However, ABA- or soil drying-induced stomatal closure of older leaves was partly restored by pretreating plants with 1-methylcyclopropene (1-MCP), which can antagonize ethylene receptors, or by inoculating soil around the roots with the rhizobacterium Variovorax paradoxus 5C-2, which contains 1-aminocyclopropane-1-carboxylic acid (ACC)-deaminase. ACC (the immediate biosynthetic precursor of ethylene) sprays revealed higher sensitivity of stomata to ethylene in older leaves than younger leaves, despite no differences in endogenous ACC concentrations or ethylene emission. Taken together, these results indicate that the relative insensitivity of stomatal closure to ABA and soil drying in older leaves is likely due to altered stomatal sensitivity to ethylene, rather than ethylene production. To our knowledge, this is the first study to mechanistically explain diminished stomatal responses to soil moisture deficit in older leaves, and the associated reduction in leaf water-use efficiency.


Munc18c regulates insulin-stimulated glut4 translocation to the transverse tubules in skeletal muscle.
To examine the intracellular trafficking and translocation of GLUT4 in skeletal muscle, we have generated transgenic mouse lines that specifically express a GLUT4-EGFP (enhanced green fluorescent protein) fusion protein under the control of the human skeletal muscle actin promoter. These transgenic mice displayed EGFP fluorescence restricted to skeletal muscle and increased glucose tolerance characteristic of enhanced insulin sensitivity. The GLUT4-EGFP protein localized to the same intracellular compartment as the endogenous GLUT4 protein and underwent insulin- and exercise-stimulated translocation to both the sarcolemma and transverse-tubule membranes. Consistent with previous studies in adipocytes, overexpression of the syntaxin 4-binding Munc18c isoform, but not the related Munc18b isoform, in vivo specifically inhibited insulin-stimulated GLUT4-EGFP translocation. Surprisingly, however, Munc18c inhibited GLUT4 translocation to the transverse-tubule membrane without affecting translocation to the sarcolemma membrane. The ability of Munc18c to block GLUT4-EGFP translocation to the transverse-tubule membrane but not the sarcolemma membrane was consistent with substantially reduced levels of syntaxin 4 in the transverse-tubule membrane. Together, these data demonstrate that Munc18c specifically functions in the compartmentalized translocation of GLUT4 to the transverse-tubules in skeletal muscle. In addition, these results underscore the utility of this transgenic model to directly visualize GLUT4 translocation in skeletal muscle.


An Annotation Sparsification Strategy for 3D Medical Image Segmentation via Representative Selection and Self-Training.
Image segmentation is critical to lots of medical applications. While deep learning (DL) methods continue to improve performance for many medical image segmentation tasks, data annotation is a big bottleneck to DL-based segmentation because (1) DL models tend to need a large amount of labeled data to train, and (2) it is highly time-consuming and label-intensive to voxel-wise label 3D medical images. Significantly reducing annotation effort while attaining good performance of DL segmentation models remains a major challenge. In our preliminary experiments, we observe that, using partially labeled datasets, there is indeed a large performance gap with respect to using fully annotated training datasets. In this paper, we propose a new DL framework for reducing annotation effort and bridging the gap between full annotation and sparse annotation in 3D medical image segmentation. We achieve this by (i) selecting representative slices in 3D images that minimize data redundancy and save annotation effort, and (ii) self-training with pseudo-labels automatically generated from the base-models trained using the selected annotated slices. Extensive experiments using two public datasets (the HVSMR 2016 Challenge dataset and mouse piriform cortex dataset) show that our framework yields competitive segmentation results comparing with state-of-the-art DL methods using less than ~ 20% of annotated data.


Childhood cancer research in oxford III: The work of CCRG on ionising radiation.
High doses of ionising radiation are a known cause of childhood cancer and great public and professional interest attaches to possible links between childhood cancer and lower doses, particularly of man-made radiation. This paper describes work done by the Childhood Cancer Research Group (CCRG) on this topic METHODS: Most UK investigations have made use of the National Registry of Childhood Tumours and associated controls. Epidemiological investigations have included national incidence and mortality analyses, geographical investigations, record linkage and case-control studies. Dosimetric studies use biokinetic and dosimetric modelling. This paper reviews the work of the CCRG on the association between exposure to ionising radiation and childhood cancer, 1975-2014. The work of CCRG has been influential in developing understanding of the causes of 'clusters' of childhood cancer and the risks arising from exposure to ionising radiation both natural and man-made. Some clusters around nuclear installations have certainly been observed, but ionising radiation does not seem to be a plausible cause. The group's work has also been instrumental in discounting the hypothesis that paternal preconception irradiation was a cause of childhood cancers and has demonstrated an increased leukaemia risk for children exposed to higher levels of natural gamma-ray radiation.


Prioritizing rare variants with conditional likelihood ratios.
Prioritizing individual rare variants within associated genes or regions often consists of an ad hoc combination of statistical and biological considerations. From the statistical perspective, rare variants are often ranked using Fisher's exact p values, which can lead to different rankings of the same set of variants depending on whether 1- or 2-sided p values are used. We propose a likelihood ratio-based measure, maxLRc, for the statistical component of ranking rare variants under a case-control study design that avoids the hypothesis-testing paradigm. We prove analytically that the maxLRc is always well-defined, even when the data has zero cell counts in the 2×2 disease-variant table. Via simulation, we show that the maxLRc outperforms Fisher's exact p values in most practical scenarios considered. Using next-generation sequence data from 27 rolandic epilepsy cases and 200 controls in a region previously shown to be linked to and associated with rolandic epilepsy, we demonstrate that rankings assigned by the maxLRc and exact p values can differ substantially. The maxLRc provides reliable statistical prioritization of rare variants using only the observed data, avoiding the need to specify parameters associated with hypothesis testing that can result in ranking discrepancies across p value procedures; and it is applicable to common variant prioritization.


External Cephalic Version: ACOG Practice Bulletin, Number 221.
In the United States, there is a widespread belief that the overall cesarean birth rate is higher than necessary. Efforts are being directed toward decreasing the number of these procedures, in part by encouraging physicians to make changes in their management practices. Because breech presentations are associated with a high rate of cesarean birth, there is renewed interest in techniques such as external cephalic version (ECV) and vaginal breech delivery. The purpose of this document is to provide information about ECV by summarizing the relevant evidence presented in published studies and to make recommendations regarding its use in obstetric practice.


Analysis of the influence of Ascaris, Borrelia, Toxocara, Toxoplasma and Mycoplasma infections on the incidence and course of Perthes disease - pilot study.
It is known from medical literature that such organisms as Ascaris, Borrelia, Mycoplasma, Toxocara and Toxoplasma can cause arthritis or cause vascular changes. We studied their influence on the incidence, course and outcome of Perthes disease. Sixty-one patients treated for Perthes disease were analysed. Thirty-seven of them took part in a follow-up examination after a mean of 2.8 years post first admission. A control group consisted of 22 patients treated operatively for other reasons. Blood tests, radiographic studies and a physical examination were carried out during the first admission and the follow-up visit. Serologic tests were positive for at least one pathogen in 67.2% of the patients with Perthes disease. In the control group, the tests were positive for Borrelia in 52.2% of the patients and for Mycoplasma in 40.9%, compared to antibody rates of 17.1% and 29.3%, respectively, in the group with Perthes disease. The lack of statistically significant differences in the distribution of infected vs. not-infected children according to the Herring classification suggests the absence of influence of the pathogens on the radiographic severity of Perthes disease. There were no statistically significant differences in the range of internal rotation and abduction of the affected limb between patients with negative and positive blood tests. The radiographs failed to show statistically significant differences in the structure of proximal femur between infected and non-infected children. Patients with a diagnosis of Perthes disease did not demonstrate more frequent infection with the organisms investigated than the control group. No link was found between those infestations and the course and prognosis of Perthes disease.


Diffuse reflectance of the ocean: influence of nonuniform phytoplankton pigment profile.
For interpretating remotely sensed diffuse reflectance of stratified case 1 waters, Gordon and Clark [Appl. Opt. 19, 3428 (1980)] suggested that the reflectance of a stratified ocean is identical to that of a hypothetical homogeneous ocean with a phytoplankton pigment concentration (?C?) that is a depthweighted average of the actual depth-varying concentration [C(z)]. However, this hypothesis has not been tested experimentally or theoretically. In this paper, the hypothesis is examined with Monte Carlo simulations of radiative transfer in case 1 waters by using a refined bio-optical model of the inherent optical properties of the medium. This bio-optical model, which includes separate plankton and detrital particle absorption and scattering, parameterized by the pigment concentration, is presented and tuned to Morel's statistical analysis of the average diffuse attenuation coefficient over the euphotic zone. It provides a reasonable fit to diffuse attenuation and reflectance data of individual stations. The tratification model of Morel and Berthon [Limnol. Oceanogr. 34, 1545 (1989)] characteristic of open ocean case 1 waters and a synthetic model of somewhat stronger stratification (maximum stratification of the pigment concentration |dC/dz| asymptotically equal to 0.43 mg/m(3)/m) are tested first. Two scenarios are used to relate the inherent optical properties to the pigment profile. In the first, the particle absorption and the scattering coefficients covary with C(z) and simulations show that the maximum error in the hypothesis is less, similar 2-3% for the pigment profiles considered. In contrast, in the second scenario, the particle absorption coefficient was permitted to covary with C(z), but the scattering coefficient was independent of depth. Here, errors in the hypothesis of as much as 22% were observed for the stronger stratifications. Finally, a synthetic example of strong stratification |dC/dz|, as large as 8.9 mg/m(3)/m) is examined, and errors in the hypothesis of the order of 20-25% are found when both the particle absorption and the scattering covary with C; however, for the depth-independent particle scattering case, the hypothesis can lead to large errors in R. Interestingly, for both scenarios, the ratio of reflectances at two wavelengths shows a much smaller deviation from the hypothesis than the reflectance itself.


The relationship of socio-economic status and access to minimum expected therapy among female breast cancer patients in the National Cancer Institute Black-White Cancer Survival Study.
Black women are more likely to be diagnosed with later stage breast cancer and have higher mortality rates from breast cancer than white women. To determine whether cancer treatment varies for white and black women, we analyzed data from the National Cancer Institute (NCI) Black-White Cancer Survival Study (BWCSS). Data from hospital medical records, central review of histology slides, and patient interviews on 861 breast cancer cases (in situ and invasive) were examined. Minimum expected therapy was defined for each disease stage as a basic minimum course of treatment that incorporated current practice, state-of-the-art knowledge, and recommendations advanced by NIH Consensus Conferences up to and including the one held in 1985. Patients in this study were diagnosed during 1985-1986. Using logistic regression techniques, those who received at least the minimum expected therapy were compared to those who did not. Thirty-six percent of the patients with late stage disease did not receive minimum expected therapy compared to four percent of the patients with early stage disease. Older women and women with no usual source of care were significantly less likely to receive minimum expected therapy. Overall, 21% of black women did not receive minimum expected therapy compared to 15% of white women.


Green tea attenuates diabetes induced Maillard-type fluorescence and collagen cross-linking in the heart of streptozotocin diabetic rats.
The enhanced myocardial collagen content, collagen glycation and the resulting advanced glycation end products (AGE) which exhibit the characteristics of increased cross-linking are proposed for the stiffness of myocardium in diabetes. To explore the cardioprotective effect of green tea in diabetes, we study the effect of green tea extract on myocardial collagen characteristics in streptozotocin diabetic rats. The effect of green tea on marker enzymes in serum and cardiac tissues were also assayed to understand the extent of protection. Six weeks after the diabetes induction, diabetic rats were treated with green tea extract [300 mg (kg body weight)(-1)day(-1)] for 4 weeks. AGE were determined by fluorescence assay and cross-linking of collagen by solubility measurement while collagen content was measured by biochemical assay. The activities of aspartate transaminase (AST), lactate dehydrogenase (LDH) and creatine kinase (CPK) were measured by biochemical assay. The increase in blood glucose, glycated hemoglobin and systolic blood pressure in diabetic rats were reduced upon green tea treatment. The activities of AST, LDH and CPK were significantly increased in serum whereas decreased in cardiac tissues in diabetic rats representing the cardiac damage. Administration of green tea to diabetic rats significantly ameliorates these enzyme activities. There was no significant difference in the myocardial collagen content among the experimental rats. A significant (P<0.05) increase in collagen linked Maillard-type fluorescence and decrease in collagen solubility in the myocardium of diabetic rats as compared to control rats (0.955+/-0.02 versus 0.683+/-0.04 and 30+/-1.41 versus 45.17+/-1.17, respectively) indicates the increase in advanced glycation end products formation and degree of collagen cross-linking. Green tea administration to diabetic rats significantly (P<0.05) decreased the fluorescence (0.73+/-0.02) whereas increased the solubility of collagen (41.5+/-1.04) indicating the reduction in advanced glycation end products and collagen cross-linking. The present study reveals that green tea by ameliorating myocardial collagen characteristics may provide a therapeutic option in the treatment of cardiovascular complications of diabetes.


Gene expression patterns in human liver cancers.
Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Using cDNA microarrays to characterize patterns of gene expression in HCC, we found consistent differences between the expression patterns in HCC compared with those seen in nontumor liver tissues. The expression patterns in HCC were also readily distinguished from those associated with tumors metastatic to liver. The global gene expression patterns intrinsic to each tumor were sufficiently distinctive that multiple tumor nodules from the same patient could usually be recognized and distinguished from all the others in the large sample set on the basis of their gene expression patterns alone. The distinctive gene expression patterns are characteristic of the tumors and not the patient; the expression programs seen in clonally independent tumor nodules in the same patient were no more similar than those in tumors from different patients. Moreover, clonally related tumor masses that showed distinct expression profiles were also distinguished by genotypic differences. Some features of the gene expression patterns were associated with specific phenotypic and genotypic characteristics of the tumors, including growth rate, vascular invasion, and p53 overexpression.


Neuroticism modulates brain visuo-vestibular and anxiety systems during a virtual rollercoaster task.
Different lines of research suggest that anxiety-related personality traits may influence the visual and vestibular control of balance, although the brain mechanisms underlying this effect remain unclear. To our knowledge, this is the first functional magnetic resonance imaging (fMRI) study that investigates how individual differences in neuroticism and introversion, two key personality traits linked to anxiety, modulate brain regional responses and functional connectivity patterns during a fMRI task simulating self-motion. Twenty-four healthy individuals with variable levels of neuroticism and introversion underwent fMRI while performing a virtual reality rollercoaster task that included two main types of trials: (1) trials simulating downward or upward self-motion (vertical motion), and (2) trials simulating self-motion in horizontal planes (horizontal motion). Regional brain activity and functional connectivity patterns when comparing vertical versus horizontal motion trials were correlated with personality traits of the Five Factor Model (i.e., neuroticism, extraversion-introversion, openness, agreeableness, and conscientiousness). When comparing vertical to horizontal motion trials, we found a positive correlation between neuroticism scores and regional activity in the left parieto-insular vestibular cortex (PIVC). For the same contrast, increased functional connectivity between the left PIVC and right amygdala was also detected as a function of higher neuroticism scores. Together, these findings provide new evidence that individual differences in personality traits linked to anxiety are significantly associated with changes in the activity and functional connectivity patterns within visuo-vestibular and anxiety-related systems during simulated vertical self-motion. Hum Brain Mapp 38:715-726, 2017. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.


An Internet of Things Based Bed-Egress Alerting Paradigm Using Wearable Sensors in Elderly Care Environment.
The lack of healthcare staff and increasing proportions of elderly population is alarming. The traditional means to look after elderly has resulted in 255,000 reported falls (only within UK). This not only resulted in extensive aftercare needs and surgeries (summing up to £4.4 billion) but also in added suffering and increased mortality. In such circumstances, the technology can greatly assist by offering automated solutions for the problem at hand. The proposed work offers an Internet of things (IoT) based patient bed-exit monitoring system in clinical settings, capable of generating a timely response to alert the healthcare workers and elderly by analyzing the wireless data streams, acquired through wearable sensors. This work analyzes two different datasets obtained from divergent families of sensing technologies, i.e., smartphone-based accelerometer and radio frequency identification (RFID) based accelerometer. The findings of the proposed system show good efficacy in monitoring the bed-exit and discriminate other ambulating activities. Furthermore, the proposed work manages to keep the average end-to-end system delay (i.e., communications of sensed data to Data Sink (DS)/Control Center (CC) + machine-based feature extraction and class identification + feedback communications to a relevant healthcare worker/elderly) below 1 10 th of a second.


Alternative Polyadenylation: Another Foe in Cancer.
Advancements in sequencing and transcriptome analysis methods have led to seminal discoveries that have begun to unravel the complexity of cancer. These studies are paving the way toward the development of improved diagnostics, prognostic predictions, and targeted treatment options. However, it is clear that pieces of the cancer puzzle are still missing. In an effort to have a more comprehensive understanding of the development and progression of cancer, we have come to appreciate the value of the noncoding regions of our genomes, partly due to the discovery of miRNAs and their significance in gene regulation. Interestingly, the miRNA-mRNA interactions are not solely dependent on variations in miRNA levels. Instead, the majority of genes harbor multiple polyadenylation signals on their 3' UTRs (untranslated regions) that can be differentially selected on the basis of the physiologic state of cells, resulting in alternative 3' UTR isoforms. Deregulation of alternative polyadenylation (APA) has increasing interest in cancer research, because APA generates mRNA 3' UTR isoforms with potentially different stabilities, subcellular localizations, translation efficiencies, and functions. This review focuses on the link between APA and cancer and discusses the mechanisms as well as the tools available for investigating APA events in cancer. Overall, detection of deregulated APA-generated isoforms in cancer may implicate some proto-oncogene activation cases of unknown causes and may help the discovery of novel cases; thus, contributing to a better understanding of molecular mechanisms of cancer. Mol Cancer Res; 14(6); 507-17. ©2016 AACR.


A cohort study investigating patient expectations and satisfaction outcomes in men undergoing robotic assisted radical prostatectomy.
Robotic assisted radical prostatectomy (RARP) is gaining widespread acceptance for the management of localized prostate cancer. However, data regarding patient expectations and satisfaction outcomes after RARP are scarce. We developed a structured program for preoperative education and evidence-based counseling using a multi-disciplinary team approach and measured its impact on patient satisfaction in a cohort of 377 consecutive patients who underwent RARP at our institution. Responses regarding overall, sexual, and continence satisfaction were assessed. Fifty percent of our patient cohort replied to the questionnaire assessments. Ninety-three percent of responding patients expressed overall satisfaction after RARP with only 0.5% expressing regret at having had the operation. Biochemical recurrence and lack of continence correlated significantly with low levels of satisfaction, though sexual function was not significantly different among those satisfied and those not. Most patients (97%) valued oncologic outcome as their top priority, with regaining of urinary control being the commonest second priority (60%). RARP appears to be associated with a high degree of patient satisfaction in a cohort of patients subjected to a structured preoperative education and counseling program. Oncologic outcomes are most important to these patients and have the largest influence on satisfaction scores.


Presentation for care and antenatal management of HIV in the UK, 2009-2014.
Despite very low rates of vertical transmission of HIV in the UK overall, rates are higher among women starting antenatal antiretroviral therapy (ART) late. We investigated the timing of key elements of the care of HIV-positive pregnant women [antenatal care booking, HIV laboratory assessment (CD4 count and HIV viral load) and antenatal ART initiation], to assess whether clinical practice is changing in line with recommendations, and to investigate factors associated with delayed care. We used the UK's National Study of HIV in Pregnancy and Childhood for 2009-2014. Data were analysed by fitting logistic regression and Cox proportional hazards models. A total of 5693 births were reported; 79.5% were in women diagnosed with HIV prior to that pregnancy. Median gestation at antenatal booking was 12.1 weeks [interquartile range (IQR) 10.0-15.6 weeks] and booking was significantly earlier during 2012-2014 vs. 2009-2011 (P < 0.001), although only in previously diagnosed women. Overall, 42.2% of pregnancies were booked late (≥ 13 gestational weeks). Among women not already on treatment, antenatal ART commenced at a median of 21.4 (IQR18.1-24.5) weeks and started significantly earlier in the most recent time period (P < 0.001). Compared with previously diagnosed women, those newly diagnosed during the current pregnancy booked later for antenatal care and started antenatal ART later (both P < 0.001). Multivariable analyses revealed demographic variations in access to or uptake of care, with groups including migrants and parous women initiating care later. Although women are accessing antenatal and HIV care earlier in pregnancy, some continue to face barriers to timely initiation of antenatal care and ART.


Prophylactic HPV vaccination: past, present, and future.
Human papillomavirus (HPV) is the necessary cause of cervical cancer, the fourth most common cancer and cause of cancer-related death in females worldwide. HPV also causes anal, vaginal, vulvar, penile, and oropharyngeal cancer. Prophylactic HPV vaccines based on recombinantly expressed virus-like particles have been developed. Two first-generation, U.S. Food and Drug Administration (FDA)-approved vaccines prevent infections and disease caused by HPV16 and HPV18, the two HPV genotypes that cause approximately 70% of cervical cancer, and one of these vaccines also prevents HPV6 and HPV11, the two HPV genotypes that cause 90% of genital warts. A next-generation vaccine, recently approved by the U.S. FDA, targets HPV16, HPV18, and five additional HPV genotypes that together causes approximately 90% of cervical cancer as well as HPV6 and HPV11. In clinical trials, these vaccines have shown high levels of efficacy against disease and infections caused by the targeted HPV genotypes in adolescent females and males and older females. Data indicate population effectiveness, and therefore cost effectiveness, is highest in HPV-naive young females prior to becoming sexually active. Countries that implemented HPV vaccination before 2010 have already experienced decreases in population prevalence of targeted HPV genotypes and related anogenital diseases in women and via herd protection in heterosexual men. Importantly, after more than 100 million doses given worldwide, HPV vaccination has demonstrated an excellent safety profile. With demonstrated efficacy, cost-effectiveness, and safety, universal HPV vaccination of all young, adolescent women, and with available resources at least high-risk groups of men, should be a global health priority. Failure to do so will result in millions of women dying from avertable cervical cancers, especially in low- and middle-income countries, and many thousands of women and men dying from other HPV-related cancers.


Impact of dental cement on the peri-implant biofilm-microbial comparison of two different cements in an in vivo observational study.
The type of cement used in cemented fixed implant-supported restorations influences formation of undetected excess cement and composition of the peri-implant biofilm. Excess cement and dysbiosis of the biofilm involve the risk of peri-implant inflammation. The aim of the study was to investigate the impact of two different cements on the peri-implant biofilm and inflammation. In an observational study, the suprastructures of 34 patients with cemented fixed implant-supported restorations were revised. In 20 patients, a methacrylate cement (Premier Implant cement [PIC]) and in 14 patients, a zinc oxide eugenol cement (Temp Bond [TB]) were used. After revision, TB was used for recementation. During revision and follow-up after 1 year, microbial samples were obtained. Excess cement was found in 12 (60%) of the 20 patients with PIC. Suppuration was observed in two (25%) implants with PIC without excess cement (PIC-) and in all 12 (100%) implants with PIC and excess cement (PIC+). Implants cemented with TB had neither excess cement nor suppuration. The taxonomic analysis of the microbial samples revealed an accumulation of periodontal pathogens in the PIC patients independent of the presence of excess cement. Significantly, fewer oral pathogens occurred in patients with TB compared to patients with PIC. TB was used in all cases (PIC and TB) for recementation. In the follow-up check, suppuration was not found around any of the implants with PIC-, only around one implant with PIC+ and around one implant with TB. Bacterial species associated with severe periodontal infections that were abundant in PIC- and PIC+ samples before the revision were reduced after 1 year to levels found in the TB samples. The revision and recementation with TB had a positive effect on the peri-implant biofilm in cases with PIC. The cementation of suprastructures on implants with TB is an alternative method to be considered.


Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study).
The incidence of stroke is predicted to rise because of the rapidly ageing population. However, over the past two decades, findings of randomised trials have identified several interventions that are effective in prevention of stroke. Reliable data on time-trends in stroke incidence, major risk factors, and use of preventive treatments in an ageing population are required to ascertain whether implementation of preventive strategies can offset the predicted rise in stroke incidence. We aimed to obtain these data. We ascertained changes in incidence of transient ischaemic attack and stroke, risk factors, and premorbid use of preventive treatments from 1981-84 (Oxford Community Stroke Project; OCSP) to 2002-04 (Oxford Vascular Study; OXVASC). Of 476 patients with transient ischaemic attacks or strokes in OXVASC, 262 strokes and 93 transient ischaemic attacks were incident events. Despite more complete case-ascertainment than in OCSP, age-adjusted and sex-adjusted incidence of first-ever stroke fell by 29% (relative incidence 0.71, 95% CI 0.61-0.83, p=0.0002). Incidence declined by more than 50% for primary intracerebral haemorrhage (0.47, 0.27-0.83, p=0.01) but was unchanged for subarachnoid haemorrhage (0.83, 0.44-1.57, p=0.57). Thus, although 28% more incident strokes (366 vs 286) were expected in OXVASC due to demographic change alone (33% increase in those aged 75 or older), the observed number fell (262 vs 286). Major reductions were recorded in mortality rates for incident stroke (0.63, 0.44-0.90, p=0.02) and in incidence of disabling or fatal stroke (0.60, 0.50-0.73, p<0.0001), but no change was seen in case-fatality due to incident stroke (17.2% vs 17.8%; age and sex adjusted relative risk 0.85, 95% CI 0.57-1.28, p=0.45). Comparison of premorbid risk factors revealed substantial reductions in the proportion of smokers, mean total cholesterol, and mean systolic and diastolic blood pressures and major increases in premorbid treatment with antiplatelet, lipid-lowering, and blood pressure lowering drugs (all p<0.0001). The age-specific incidence of major stroke in Oxfordshire has fallen by 40% over the past 20 years in association with increased use of preventive treatments and major reductions in premorbid risk factors.


Identifying risk factors for the development of sepsis during adult severe malaria.
Severe falciparum malaria can be compounded by bacterial sepsis, necessitating antibiotics in addition to anti-malarial treatment. The objective of this analysis was to develop a prognostic model to identify patients admitted with severe malaria at higher risk of developing bacterial sepsis. A retrospective data analysis using trial data from the South East Asian Quinine Artesunate Malaria Trial. Variables correlating with development of clinically defined sepsis were identified by univariable analysis, and subsequently included into a multivariable logistic regression model. Internal validation was performed by bootstrapping. Discrimination and goodness-of-fit were assessed using the area under the curve (AUC) and a calibration plot, respectively. Of the 1187 adults with severe malaria, 86 (7.3%) developed clinical sepsis during admission. Predictors for developing sepsis were: female sex, high blood urea nitrogen, high plasma anion gap, respiratory distress, shock on admission, high parasitaemia, coma and jaundice. The AUC of the model was 0.789, signifying modest differentiation for identifying patients developing sepsis. The model was well-calibrated (Hosmer-Lemeshow Chi squared = 1.02). The 25th percentile of the distribution of risk scores among those who developed sepsis could identify a high-risk group with a sensitivity and specificity of 70.0 and 69.4%, respectively. The proposed model identifies patients with severe malaria at risk of developing clinical sepsis, potentially benefiting from antibiotic treatment in addition to anti-malarials. The model will need further evaluation with more strictly defined bacterial sepsis as outcome measure.


Effect of Financial Bonus Size, Loss Aversion, and Increased Social Pressure on Physician Pay-for-Performance: A Randomized Clinical Trial and Cohort Study.
Despite limited effectiveness of pay-for-performance (P4P), payers continue to expand P4P nationally. To test whether increasing bonus size or adding the behavioral economic principles of increased social pressure (ISP) or loss aversion (LA) improves the effectiveness of P4P. Parallel studies conducted from January 1 to December 31, 2016, consisted of a randomized clinical trial with patients cluster-randomized by practice site to an active control group (larger bonus size [LBS] only) or to groups with 1 of 2 behavioral economic interventions added and a cohort study comparing changes in outcomes among patients of physicians receiving an LBS with outcomes in propensity-matched physicians not receiving an LBS. A total of 8118 patients attributed to 66 physicians with 1 of 5 chronic conditions were treated at Advocate HealthCare, an integrated health system in Illinois. Data were analyzed using intention to treat and multiple imputation from February 1, 2017, through May 31, 2018. Physician participants received an LBS increased by a mean of $3355 per physician (LBS-only group); prefunded incentives to elicit LA and an LBS; or increasing proportion of a P4P bonus determined by group performance from 30% to 50% (ISP) and an LBS. The proportion of 20 evidence-based quality measures achieved at the patient level. A total of 86 physicians were eligible for the randomized trial. Of these, 32 were excluded because they did not have unique attributed patients. Fifty-four physicians were randomly assigned to 1 of 3 groups, and 33 physicians (54.5% male; mean [SD] age, 57 [10] years) and 3747 patients (63.6% female; mean [SD] age, 64 [18] years) were included in the final analysis. Nine physicians and 864 patients were randomized to the LBS-only group, 13 physicians and 1496 patients to the LBS plus ISP group, and 11 physicians and 1387 patients to the LBS plus LA group. Physician characteristics did not differ significantly by arm, such as mean (SD) physician age ranging from 56 (9) to 59 (9) years, and sex (6 [46.2%] to 6 [66.7%] male). No differences were found between the LBS-only and the intervention groups (adjusted odds ratio [aOR] for LBS plus LA vs LBS-only, 0.86 [95% CI, 0.65-1.15; P = .31]; aOR for LBS plus ISP vs LBS-only, 0.95 [95% CI, 0.64-1.42; P = .81]; and aOR for LBS plus ISP vs LBS plus LA, 1.10 [95% CI, 0.75-1.61; P = .62]). Increased bonus size was associated with a greater increase in evidence-based care relative to the comparison group (risk-standardized absolute difference-in-differences, 3.2 percentage points; 95% CI, 1.9-4.5 percentage points; P < .001). Increased bonus size was associated with significantly improved quality of care relative to a comparison group. Adding ISP and opportunities for LA did not improve quality. ClinicalTrials.gov Identifier: NCT02634879.


Factors affecting the introduction of new vaccines to poor nations: a comparative study of the Haemophilus influenzae type B and hepatitis B vaccines.
A major effort to introduce new vaccines into poor nations of the world was initiated in recent years with the help of the GAVI alliance. The first vaccines introduced have been the Haemophilus influenzae type B (Hib) and the hepatitis B (Hep B) vaccines. The introduction of these vaccines during the first phase of GAVI's operations demonstrated considerable variability. We set out to study the factors affecting the introduction of these vaccines. The African Region (AFRO), where new vaccines were introduced to a substantial number of countries during the first phase of GAVI's funding, was selected for this study. GAVI-eligible AFRO countries with a population of 0.5 million or more were included in the study. Countries were analyzed and compared for new vaccine introduction, healthcare indicators, financial indicators related to healthcare and country-level Governance Indicators, using One Way ANOVA, correlation analysis and Qualitative Comparative Analysis (QCA). Introduction of new vaccines into AFRO nations was associated primarily with high country-level Governance Indicator scores. The use of individual Governance Indicator scores, as well as a combined Governance Indicator score we developed, demonstrated similar results. Our study results indicate that good country-level governance is an imperative pre-requisite for the successful early introduction of new vaccines into poor African nations. Enhanced support measures may be required to effectively introduce new vaccines to countries with low governance scores. The combined governance score we developed may thus constitute a useful tool for helping philanthropic organizations make decisions regarding the type of support needed by different countries to achieve success.


Translating insights into tumor evolution to clinical practice: promises and challenges.
Accelerating technological advances have allowed the widespread genomic profiling of tumors. As yet, however, the vast catalogues of mutations that have been identified have made only a modest impact on clinical medicine. Massively parallel sequencing has informed our understanding of the genetic evolution and heterogeneity of cancers, allowing us to place these mutational catalogues into a meaningful context. Here, we review the methods used to measure tumor evolution and heterogeneity, and the potential and challenges for translating the insights gained to achieve clinical impact for cancer therapy, monitoring, early detection, risk stratification, and prevention. We discuss how tumor evolution can guide cancer therapy by targeting clonal and subclonal mutations both individually and in combination. Circulating tumor DNA and circulating tumor cells can be leveraged for monitoring the efficacy of therapy and for tracking the emergence of resistant subclones. The evolutionary history of tumors can be deduced for late-stage cancers, either directly by sampling precursor lesions or by leveraging computational approaches to infer the timing of driver events. This approach can identify recurrent early driver mutations that represent promising avenues for future early detection strategies. Emerging evidence suggests that mutational processes and complex clonal dynamics are active even in normal development and aging. This will make discriminating developing malignant neoplasms from normal aging cell lineages a challenge. Furthermore, insight into signatures of mutational processes that are active early in tumor evolution may allow the development of cancer-prevention approaches. Research and clinical studies that incorporate an appreciation of the complex evolutionary patterns in tumors will not only produce more meaningful genomic data, but also better exploit the vulnerabilities of cancer, resulting in improved treatment outcomes.


Gout.
This issue provides a clinical overview of gout, focusing on prevention and screening, diagnosis, and treatment. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.


Codon swapping of zinc finger nucleases confers expression in primary cells and in vivo from a single lentiviral vector.
Zinc finger nucleases (ZFNs) are promising tools for genome editing for biotechnological as well as therapeutic purposes. Delivery remains a major issue impeding targeted genome modification. Lentiviral vectors are highly efficient for delivering transgenes into cell lines, primary cells and into organs, such as the liver. However, the reverse transcription of lentiviral vectors leads to recombination of homologous sequences, as found between and within ZFN monomers. We used a codon swapping strategy to both drastically disrupt sequence identity between ZFN monomers and to reduce sequence repeats within a monomer sequence. We constructed lentiviral vectors encoding codon-swapped ZFNs or unmodified ZFNs from a single mRNA transcript. Cell lines, primary hepatocytes and newborn rats were used to evaluate the efficacy of integrative-competent (ICLV) and integrative-deficient (IDLV) lentiviral vectors to deliver ZFNs into target cells. We reduced total identity between ZFN monomers from 90.9% to 61.4% and showed that a single ICLV allowed efficient expression of functional ZFNs targeting the rat UGT1A1 gene after codon-swapping, leading to much higher ZFN activity in cell lines (up to 7-fold increase compared to unmodified ZFNs and 60% activity in C6 cells), as compared to plasmid transfection or a single ICLV encoding unmodified ZFN monomers. Off-target analysis located several active sites for the 5-finger UGT1A1-ZFNs. Furthermore, we reported for the first time successful ZFN-induced targeted DNA double-strand breaks in primary cells (hepatocytes) and in vivo (liver) after delivery of a single IDLV encoding two ZFNs. These results demonstrate that a codon-swapping approach allowed a single lentiviral vector to efficiently express ZFNs and should stimulate the use of this viral platform for ZFN-mediated genome editing of primary cells, for both ex vivo or in vivo applications.


Real-time quantitative PCR for human herpesvirus 6 DNA.
The diagnosis of human herpesvirus 6 (HHV-6) infection represents a complex issue because the most widely used diagnostic tools, such as immunoglobulin G antibody titer determination and qualitative DNA PCR with blood cells, are unable to distinguish between latent (clinically silent) and active (often clinically relevant) infection. We have developed a new, highly sensitive, quantitative PCR assay for the accurate measurement of HHV-6 DNA in tissue-derived cell suspensions and body fluids. The test uses a 5' nuclease, fluorogenic assay combined with real-time detection of PCR amplification products with the ABI PRISM 7700 sequence detector system. The sensitivity of this method is equal to the sensitivity of a nested PCR protocol (lower detection limit, 1 viral genome equivalent/test) for both the A and the B HHV-6 subgroups and shows a wider dynamic range of detection (from 1 to 10(6) viral genome equivalents/test) and a higher degree of accuracy, repeatability, and reproducibility compared to those of a standard quantitative-competitive PCR assay developed with the same reference DNA molecule. The novel technique is versatile, showing the same sensitivity and dynamic range with viral DNA extracted from different fluids (i.e., culture medium or plasma) or from tissue-derived cell suspensions. Furthermore, by virtue of its high-throughput format, this method is well suited for large epidemiological surveys.


Patterning of the C. elegans 1 degrees vulval lineage by RAS and Wnt pathways.
In C. elegans, the descendants of the 1 degrees vulval precursor cell (VPC) establish a fixed spatial pattern of two different cell fates: E-F-F-E. The two inner granddaughters attach to the somatic gonadal anchor cell (AC) and generate four vulF cells, while the two outer granddaughters produce four vulE progeny. zmp-1::GFP, a molecular marker that distinguishes these two fates, is expressed in vulE cells, but not vulF cells. We demonstrate that a short-range AC signal is required to ensure that the pattern of vulE and vulF fates is properly established. In addition, signaling between the inner and outer 1 degrees VPC descendants, as well as intrinsic polarity of the 1 degrees VPC daughters, is involved in the asymmetric divisions of the 1 degrees VPC daughters and the proper orientation of the outcome. Finally, we provide evidence that RAS signaling is used during this new AC signaling event, while the Wnt receptor LIN-17 appears to mediate signaling between the inner and outer 1 degrees VPC descendants.


Crystal Structure of the DNA Deaminase APOBEC3B Catalytic Domain.
Functional and deep sequencing studies have combined to demonstrate the involvement of APOBEC3B in cancer mutagenesis. APOBEC3B is a single-stranded DNA cytosine deaminase that functions normally as a nuclear-localized restriction factor of DNA-based pathogens. However, it is overexpressed in cancer cells and elicits an intrinsic preference for 5'-TC motifs in single-stranded DNA, which is the most frequently mutated dinucleotide in breast, head/neck, lung, bladder, cervical, and several other tumor types. In many cases, APOBEC3B mutagenesis accounts for the majority of both dispersed and clustered (kataegis) cytosine mutations. Here, we report the first structures of the APOBEC3B catalytic domain in multiple crystal forms. These structures reveal a tightly closed active site conformation and suggest that substrate accessibility is regulated by adjacent flexible loops. Residues important for catalysis are identified by mutation analyses, and the results provide insights into the mechanism of target site selection. We also report a nucleotide (dCMP)-bound crystal structure that informs a multistep model for binding single-stranded DNA. Overall, these high resolution crystal structures provide a framework for further mechanistic studies and the development of novel anti-cancer drugs to inhibit this enzyme, dampen tumor evolution, and minimize adverse outcomes such as drug resistance and metastasis.


Indicators of anxiety and depression in women with the fragile X premutation: assessment of a clinical sample.
Current research suggests that depression and anxiety may be common problems in women with the fragile X (FMR1) premutation. To learn more about this in a clinical setting, we asked 33 women with the FMR1 premutation and 20 women without the FMR1 premutation to complete the Brief Carroll Depression Scale (Brief CDS) and the Multidimensional Anxiety Questionnaire (MAQ) and to provide information about mental health medication use. Questionnaire findings were compared between groups and with normative samples. Trinucleotide (CGG) repeat counts were also correlated to checklist findings. Both women with the FMR1 premutation and the comparison group had high current mental health medication use (33% vs. 35%). Approximately 1/3 of the women from both groups had high Brief CDS Total T-scores (33% vs. 30%). More women with the FMR1 premutation had at least one elevated MAQ Total or sub-scale T-score than the comparison group (39% vs. 10%, P = 0.03). Twenty-one per cent of women with the FMR1 premutation had all three of the indicators of distress targeted in this study vs. none of the women in the comparison samples (P < 0.05). There was no statistically significant correlation between CGG repeat size and abnormal checklist findings using the Spearman rank correlation, although a higher percentage of women with >100 CGG repeats (57%) had an elevated Brief CDS Total T-score than women with <or=100 CGG repeats (16%) (P = 0.02). More women with >100 CGG repeats also had all three indicators of anxiety and depression (P = 0.03). Women with the FMR1 premutation appear to have a high incidence of depression and increased symptoms of anxiety. Screening tools like the Brief CDS and the MAQ may be useful to identify these women in the clinic setting. Positive identification could lead to increased mental health care and treatment.


'Will I be able to have a baby?' Results from online focus group discussions with childhood cancer survivors in Sweden.
What do adolescent and young adult survivors of childhood cancer think about the risk of being infertile? The potential infertility, as well as the experience of having had cancer, affects well-being, intimate relationships and the desire to have children in the future. Many childhood cancer survivors want to have children and worry about possible infertility. For this qualitative study with a cross-sectional design, data were collected through 39 online focus group discussions during 2013. Cancer survivors previously treated for selected diagnoses were identified from The Swedish Childhood Cancer Register (16-24 years old at inclusion, ≥5 years after diagnosis) and approached regarding study participation. Online focus group discussions of mixed sex (n = 133) were performed on a chat platform in real time. Texts from the group discussions were analysed using qualitative content analysis. The analysis resulted in the main category Is it possible to have a baby? including five generic categories: Risk of infertility affects well-being, Dealing with possible infertility, Disclosure of possible infertility is a challenge, Issues related to heredity and Parenthood may be affected. The risk of infertility was described as having a negative impact on well-being and intimate relationships. Furthermore, the participants described hesitation about becoming a parent due to perceived or anticipated physical and psychological consequences of having had cancer. Given the sensitive topic of the study, the response rate (36%) is considered acceptable. The sample included participants who varied with regard to received fertility-related information, current fertility status and concerns related to the risk of being infertile. The results may be transferred to similar contexts with other groups of patients of childbearing age and a risk of impaired fertility due to disease. The findings imply that achieving parenthood, whether or not with biological children, is an area that needs to be addressed by health care services. The study was financially supported by The Cancer Research Foundations of Radiumhemmet, The Swedish Childhood Cancer Foundation and the Doctoral School in Health Care Science, Karolinska Institutet. The authors report no conflicts of interest.


Kinematic and dynamic gait compensations resulting from knee instability in a rat model of osteoarthritis.
Osteoarthritis (OA) results in pain and disability; however, preclinical OA models often focus on joint-level changes. Gait analysis is one method used to evaluate both preclinical OA models and OA patients. The objective of this study is to describe spatiotemporal and ground reaction force changes in a rat medial meniscus transection (MMT) model of knee OA and to compare these gait measures with assays of weight bearing and tactile allodynia. Sixteen rats were used in the study. The medial collateral ligament (MCL) was transected in twelve Lewis rats (male, 200 to 250 g); in six rats, the medial meniscus was transected, and the remaining six rats served as sham controls. The remaining four rats served as naïve controls. Gait, weight-bearing as measured by an incapacitance meter, and tactile allodynia were assessed on postoperative days 9 to 24. On day 28, knee joints were collected for histology. Cytokine concentrations in the serum were assessed with a 10-plex cytokine panel. Weight bearing was not affected by sham or MMT surgery; however, the MMT group had decreased mechanical paw-withdrawal thresholds in the operated limb relative to the contralateral limb (P = 0.017). The gait of the MMT group became increasingly asymmetric from postoperative days 9 to 24 (P = 0.020); moreover, MMT animals tended to spend more time on their contralateral limb than their operated limb while walking (P < 0.1). Ground reaction forces confirmed temporal shifts in symmetry and stance time, as the MMT group had lower vertical and propulsive ground reaction forces in their operated limb relative to the contralateral limb, naïve, and sham controls (P < 0.05). Levels of interleukin 6 in the MMT group tended to be higher than naïve controls (P = 0.072). Histology confirmed increased cartilage damage in the MMT group, consistent with OA initiation. Post hoc analysis revealed that gait symmetry, stance time imbalance, peak propulsive force, and serum interleukin 6 concentrations had significant correlations to the severity of cartilage lesion formation. These data indicate significant gait compensations were present in the MMT group relative to medial collateral ligament (MCL) injury (sham) alone and naïve controls. Moreover, these data suggest that gait compensations are likely driven by meniscal instability and/or cartilage damage, and not by MCL injury alone.


'Dual' peptidyl-oligonucleotide conjugates: Role of conformational flexibility in catalytic cleavage of RNA.
Traditional therapeutic interventions against abnormal gene expression in disease states at the level of expressed proteins are becoming increasingly difficult due to poor selectivity, off-target effects and associated toxicity. Upstream catalytic targeting of specific RNA sequences offers an alternative platform for drug discovery to achieve more potent and selective treatment through antisense interference with disease-relevant RNAs. We report a novel class of catalytic biomaterials, comprising amphipathic RNA-cleaving peptides placed between two RNA recognition motifs, here demonstrated to target the TΨC loop and 3'- acceptor stem of tRNAPhe. These unique peptidyl-oligonucleotide 'dual' conjugates (DCs) were created by phosphoramidate or thiol-maleimide conjugation chemistry of a TΨC-targeting oligonucleotide to the N-terminus of the amphipathic peptide sequence, followed by amide coupling of a 3'-acceptor stem-targeting oligonucleotide to the free C-terminal carboxylic acid functionality of the same peptide. Hybridization of the DCs bearing two spatially-separated recognition motifs with the target tRNAPhe placed the peptide adjacent to a single-stranded RNA region and promoted cleavage within the 'action radius' of the catalytic peptide. Up to 100% cleavage of the target tRNAPhe was achieved by the best candidate (i.e. DC6) within 4 h, when conformational flexibility was introduced into the linker regions between the peptide and oligonucleotide components. This study provides the strong position for future development of highly selective RNA-targeting agents that can potentially be used for disease-selective treatment at the level of messenger, micro, and genomic viral RNA.


Overweight, Obesity, and Postmenopausal Invasive Breast Cancer Risk: A Secondary Analysis of the Women's Health Initiative Randomized Clinical Trials.
More than two-thirds of US women are overweight or obese, placing them at increased risk for postmenopausal breast cancer. To investigate in this secondary analysis the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women's Health Initiative (WHI) clinical trials. The WHI clinical trial protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer end points in 67 142 postmenopausal women ages 50 to 79 years at 40 US clinical centers. The women were enrolled from 1993 to 1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed. Height and weight were measured at baseline, and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history, and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators. Women who were overweight and obese had an increased invasive breast cancer risk vs women of normal weight. Risk was greatest for obesity grade 2 plus 3 (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, >35.0) (hazard ratio [HR] for invasive breast cancer, 1.58; 95% CI, 1.40-1.79). A BMI of 35.0 or higher was strongly associated with risk for estrogen receptor-positive and progesterone receptor-positive breast cancers (HR, 1.86; 95% CI, 1.60-2.17) but was not associated with estrogen receptor-negative cancers. Obesity grade 2 plus 3 was also associated with advanced disease, including larger tumor size (HR, 2.12; 95% CI, 1.67-2.69; P = .02), positive lymph nodes (HR, 1.89; 95% CI, 1.46-2.45; P = .06), regional and/or distant stage (HR, 1.94; 95% CI, 1.52-2.47; P = .05), and deaths after breast cancer (HR, 2.11; 95% CI, 1.57-2.84; P < .001). Women with a baseline BMI of less than 25.0 who gained more than 5% of body weight over the follow-up period had an increased breast cancer risk (HR, 1.36; 95% CI, 1.1-1.65), but among women already overweight or obese we found no association of weight change (gain or loss) with breast cancer during follow-up. There was no effect modification of the BMI-breast cancer relationship by postmenopausal hormone therapy, and the direction of association across BMI categories was similar for never, past, and current hormone therapy use. Obesity is associated with increased invasive breast cancer risk in postmenopausal women. These clinically meaningful findings should motivate programs for obesity prevention. clinicaltrials.gov Identifier: NCT00000611.


Lack of mutation induction with exposure to 1.5 GHz electromagnetic near fields used for cellular phones in brains of Big Blue mice.
The possible mutagenic potential of exposure to 1.5 GHz electromagnetic near field (EMF) was investigated using brain tissues of Big Blue mice (BBM). Male BBM were locally exposed to EMF in the head region at 2.0, 0.67, and 0 W/kg specific absorption rate for 90 min/day, 5 days/week, for 4 weeks. No gliosis or degenerative lesions were histopathologically noted in brain tissues, and no obvious differences in Ki-67 labeling and apoptotic indices of glial cells were evident among the groups. There was no significant variation in the frequency of independent mutations of the lacI transgene in the brains. G:C to A:T transitions at CpG sites constituted the most prevalent mutations in all groups and at all time points. Deletion mutations were slightly increased in both the high and low EMF exposure groups as compared with the sham-exposed group, but the differences were not statistically significant. These findings suggest that exposure to 1.5 GHz EMF is not mutagenic to mouse brain cells and does not create any increased hazard with regard to brain tumor development.


Uptake of guidelines in the management of patients taking anticoagulants and antiplatelet agents presenting for elective surgery.
Management guidelines for patients on antithrombotic agents presenting for surgery have long been disseminated. Clinical practice, however, does not always follow published guidelines in a timely manner, despite their dissemination. This project is an audit of the management of patients on anticoagulants or antiplatelet agents presenting for elective surgery in a large metropolitan teaching hospital. An audit was conducted of the management of patients on anticoagulants or antiplatelet agents presenting for elective surgery at Westmead Hospital to determine the percentage of patients whose management complied with guidelines, and to identify the prevailing reasons for guideline deviation. This was an observational study with qualitative and quantitative aspects. Data was collected for the 102 patients who fulfilled the inclusion criteria: 55.4% of decisions by surgeons and 51.4% of decisions by anaesthetists made in this study matched guidelines; 31.4% of decisions made by anaesthetists were fully compliant with guidelines; 20% of anaesthetic decisions were unintentionally compliant and 48.6% of anaesthetic decisions were noncompliant. A variety of reasons were cited for decisions made without the use of guidelines such as other clinical imperatives, lack of guideline awareness and a belief that it is not the role of the anaesthetist to manage perioperative antithrombotic therapy, amongst others. It is evident from this audit that compliance with guidelines remains an area where there is an opportunity for further practice improvement.


Intestinal homeostasis is restored in mice following a period of intestinal growth induced by orally administered Emu Oil.
Previously, we reported that orally administered Emu Oil (EO) increases mucosal thickness in the small intestine and colon in rodent models of chemotherapy-induced mucositis and colitis. However, it remains unclear whether mucosal thickening (crypt and villus lengthening) represents a process of normal or aberrant growth. We sought to determine if villus height (VH) and crypt depth (CD) measurements returned to normal in EO-treated rats following withdrawal of EO therapy. Dark agouti rats ( n = 8/group) were gavaged daily for 10 days with water, olive oil (OO), or EO (0.5 mL or 1 mL). Groups of rats were euthanized on days 10 and 17. Intestinal weights, lengths, VH, and CD were quantified. P < 0.05 was considered significant. On day 10, jejuno-ileum weight was increased by OO (26%) and EO (0.5 mL: 15%; 1 mL: 29%) compared to water controls ( P < 0.01), which was normalized by day 17. On days 10 and 17, jejuno-ileum length was greater in OO- (12%) and EO-treated rats (0.5 mL: 8%; 1 mL: 12%; P < 0.05), relative to water controls. On day 10, OO and EO increased ileal VH (OO: 32%; 0.5 EO: 22%; EO: 35%; P < 0.01) and CD (OO: 17%; 0.5 EO: 13%; EO: 22%) compared to water controls. Importantly, however, after withdrawal of all oils, VH and CD measurements returned to normal control values. Moreover, the VH:CD ratio (potential indicator of dysplasia) remained unchanged in all experimental groups on days 10 and 17. The restoration of normal intestinal architecture following cessation of Emu Oil therapy supports its safety for application in intestinal disorders. Impact statement Uncontrolled inflammation and intestinal proliferation can predispose to the development of colorectal cancer. In previous pre-clinical studies, we demonstrated that oral administration of Emu Oil promotes intestinal repair via stimulation of the mucosa in response to tissue injury and inflammation. Therefore, it was important to determine if Emu Oil administration did not promote the precocious development of colorectal cancer. The current study revealed that Emu Oil returned indicators of intestinal proliferation back to normal values after a period of seven days. These data strongly support the safety of Emu Oil for further studies in the context of bowel inflammation.


New insight into icing and de-icing properties of hydrophobic and hydrophilic structured surfaces based on core-shell particles.
Icing is an important problem, which often leads to emergency situations in northern countries. The reduction of icing requires a detailed understanding of this process. In this work, we report on a systematic investigation of the effects of geometry and chemical properties of surfaces on the formation of an ice layer, its properties, and thawing. We compare in detail icing and ice thawing on flat and rough hydrophilic and hydrophobic surfaces. We also show advantages and disadvantages of the surfaces of each kind. We demonstrate that water condenses in a liquid form, leading to the formation of a thin continuous water layer on a hydrophilic surface. Meanwhile, separated rounded water droplets are formed on hydrophobic surfaces. As a result of slower heat exchange, the freezing of rounded water droplets on a hydrophobic surface occurs later than the freezing of the continuous water layer on a hydrophilic one. Moreover, growth of ice on hydrophobic surfaces is slower than on the hydrophilic ones, because ice grows due to the condensation of water vapor on already formed ice crystals, and not due to the condensation on the polymer surface. Rough hydrophobic surfaces also demonstrate a very low ice adhesion value, which is because of the reduced contact area with ice. The main disadvantage of hydrophobic and superhydrophobic surfaces is the pinning of water droplets on them after thawing. Flat hydrophilic poly(ethylene glycol)-modified surfaces also exhibit very low ice adhesion, which is due to the very low freezing point of the water-poly(ethylene glycol) mixtures. Water easily leaves from flat hydrophilic poly(ethylene glycol)-modified surfaces, and they quickly become dry. However, the ice growth rate on poly(ethylene glycol)-modified hydrophilic surfaces is the highest. These results indicate that neither purely (super)hydrophobic polymeric surfaces, nor "antifreeze" hydrophilic ones provide an ideal solution to the problem of icing.


How Situational Context Impacts Empathic Responses and Brain Activation Patterns.
Clinical empathy, which is defined as the ability to understand the patient's experience and feelings from the patient's perspective, is acknowledged to be an important aspect of quality healthcare. However, how work experience modulates the empathic responses and brain activation patterns in medical professions remains elusive. This fMRI study recruited one hundred female nurses, who varied the length of work experience, and examined how their neural response, functional connectivity, and subjective evaluations of valence and arousal to perceiving another individual in physical pain are modulated by the situational context in which they occur (i.e., in a hospital or at home). Participants with longer hospital terms evaluated pain as less negative in valence and arousal when occurring in a hospital context, but not in a home context. Physical pain perceived in a hospital compared to a home context produced stronger activity in the right temporoparietal junction (rTPJ). The reverse comparison resulted in an increased activity in the insula and anterior midcingulate cortex (aMCC). Mediation analysis indicated that reduced personal accomplishment, a symptom of burnout, breaks down the mediation effect of the putamen on context-dependent valence ratings. Overall, the study demonstrates how situational contexts significantly influence individuals' empathic processing, and that perceiving reward from patient care protects them from burnout. Highlights -Differences in behavior ratings and brain activations between medical practitioners perceiving others' pain in a hospital and at home.-Situational contexts significantly influence individual's empathic processing.-Perceiving rewards from patient care protects medical practitioners from burnout.-Empathy is a flexible phenomenon.


Comparison of Patient Comfort During the First Stage of Conventional Versus Modified Two-Stage Inferior Alveolar Nerve Blocks in Pediatric Patients.
Our aim was to compare the comfort of pediatric patients during the first stage of the conventional 2-stage inferior alveolar nerve block (IANB) versus the modified 2-stage IANB. This was a parallel group, single-blinded, randomized controlled trial. Pediatric patients meeting the inclusion criteria were randomly allocated to 1 of the 2 groups receiving IANB, group 1 (31 subjects) utilized a conventional 2-stage technique, and group 2 (33 subjects) utilized a modified 2-stage approach. Patient comfort was assessed indirectly by 2 observers using the Face, Legs, Activity, Cry, Consolability (FLACC) scale during the first stage of the injections. FLACC score data between the 2 groups were analyzed using the chi-square test, and interobserver reliability was measured using kappa statistics. During the first stage of the injections, lower FLACC scores of 0 indicating a relaxed/comfortable patient experience were found in 57.6% of group 2 subjects compared with only 25.8% group 1 subjects, which was a statistically significant difference (p-value .013). Interobserver reliability assessed using kappa coefficients (κ = 0.812) indicated excellent agreement. FLACC scores for the pediatric patients during the first stage of the modified 2-stage IANB technique were significantly lower than during the first stage of the conventional 2-stage IANB technique.


Meta4: a web application for sharing and annotating metagenomic gene predictions using web services.
Whole-genome shotgun metagenomics experiments produce DNA sequence data from entire ecosystems, and provide a huge amount of novel information. Gene discovery projects require up-to-date information about sequence homology and domain structure for millions of predicted proteins to be presented in a simple, easy-to-use system. There is a lack of simple, open, flexible tools that allow the rapid sharing of metagenomics datasets with collaborators in a format they can easily interrogate. We present Meta4, a flexible and extensible web application that can be used to share and annotate metagenomic gene predictions. Proteins and predicted domains are stored in a simple relational database, with a dynamic front-end which displays the results in an internet browser. Web services are used to provide up-to-date information about the proteins from homology searches against public databases. Information about Meta4 can be found on the project website, code is available on Github, a cloud image is available, and an example implementation can be seen at.