Social Robots for Hospitalized Children.
Social robots (SRs) are increasingly present in medical and educational contexts, but their use in inpatient pediatric settings has not been demonstrated in studies. In this study, we aimed to (1) describe the introduction of SR technology into the pediatric inpatient setting through an innovative partnership among a pediatric teaching hospital, robotics development, and computational behavioral science laboratories and (2) present feasibility and acceptability data. Fifty-four children ages 3 to 10 years were randomly exposed to 1 of 3 interventions: (1) interactive SR teddy bear; (2) tablet-based avatar version of the bear; or (3) plush teddy bear with human presence. We monitored intervention enrollment and completion patterns, obtained qualitative feedback on acceptability of SR use from child life-specialist stakeholders, and assessed children's positive and negative affect, anxiety, and pain intensity pre- and postintervention. The intervention was well received and appeared feasible, with 93% of those enrolled completing the study (with 80% complete parent data). Children exposed to the SR reported more positive affect relative to those who received a plush animal. SR interactions were characterized by greater levels of joyfulness and agreeableness than comparison interventions. Child life specialist stakeholders reported numerous potential benefits of SR technology in the pediatric setting. The SR appears to be an engaging tool that may provide new ways to address the emotional needs of hospitalized children, potentially increasing access to emotionally targeted interventions. Rigorous development and validation of SR technology in pediatrics could ultimately lead to scalable and cost-effective tools to improve the patient care experience.


Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases.
The clinical success of TNFalpha blocking biologics in a growing number of immune-mediated pathologies, including rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and psoriasis, confirms the importance of TNFalpha in driving chronic inflammation and represents an important step forward in the treatment of these conditions. TNFalpha blockade, however, is a treatment, rather than a cure, and is not effective in all patients or in all autoimmune diseases and further research is needed to get closer to a cure. Recently, the identification of a novel, IL-17 producing, T helper cell subset, that plays a dominant pathogenic role in animal models of autoimmunity, is a major advance on existing knowledge, although the role of these cells in human disease remains to be established. Cytokines driving angiogenesis are also important in disease chronicity and thus might be valid therapeutic targets.


Shmoos, rafts, and uropods- the many facets of cell polarity.
The recent Juan March Foundation meeting on "Regulation and functional insights in cellular polarity" focused on cellular polarity in yeasts, Dictyostelium, epithelial cells, fibroblasts, and immune cells. The molecular systems covered included membrane rafts, actin and tubulin cytoskeleton, polarized transcription, signaling, and cell-cell adhesion. Across these diverse biological and molecular systems, important general concepts emerged, including new ideas for establishing and maintaining polarity that are likely to be applicable across models and experimental systems.


Non-invasive measurement of glucocorticoids: Advances and problems.
Glucocorticoids (GCs; i.e. cortisol/corticosterone) are a central component of the stress response and thus their measurement is frequently used to evaluate the impact of stressful situations. Their metabolites from faeces of various animal species are more and more taken as a non-invasive aid to assess GC release and thus adrenocortical activity. The current literature review includes an extensive collection (1327 papers) and evaluation (see also Supplementary Tables) of the literature on faecal cortisol/corticosterone metabolite (FCM) analysis published to date. It aims at giving reference for researchers interested in implementing FCM analysis into their study or seeking to improve such methods by providing background knowledge on GC metabolism and excretion, conveying insights into methodological issues and stating caveats of FCM analysis and by highlighting prerequisites for and some examples of a successful application of such methods. Collecting faecal samples and analysing FCMs may appear simple and straightforward, but researchers have to select and apply methods correctly. They also need to be aware of the many pitfalls and potentially confounding factors and, last but not least, have to carefully interpret results. Applied properly, measurement of FCMs is a powerful non-invasive tool in a variety of research areas, such as (stress) biology, ethology, ecology, animal conservation and welfare, but also biomedicine.


Rural and Urban Differences in Air Quality, 2008-2012, and Community Drinking Water Quality, 2010-2015 - United States.
The places in which persons live, work, and play can contribute to the development of adverse health outcomes. Understanding the differences in risk factors in various environments can help to explain differences in the occurrence of these outcomes and can be used to develop public health programs, interventions, and policies. Efforts to characterize urban and rural differences have largely focused on social and demographic characteristics. A paucity of national standardized environmental data has hindered efforts to characterize differences in the physical aspects of urban and rural areas, such as air and water quality. 2008-2012 for air quality and 2010-2015 for water quality. Since 2002, CDC's National Environmental Public Health Tracking Program has collaborated with federal, state, and local partners to gather standardized environmental data by creating national data standards, collecting available data, and disseminating data to be used in developing public health actions. The National Environmental Public Health Tracking Network (i.e., the tracking network) collects data provided by national, state, and local partners and includes 21 health outcomes, exposures, and environmental hazards. To assess environmental factors that affect health, CDC analyzed three air-quality measures from the tracking network for all counties in the contiguous United States during 2008-2012 and one water-quality measure for 26 states during 2010-2015. The three air-quality measures include 1) total number of days with fine particulate matter (PM2.5) levels greater than the U.S. Environmental Protection Agency's (EPA's) National Ambient Air Quality Standards (NAAQS) for 24-hour average PM2.5 (PM2.5 days); 2) mean annual average ambient concentrations of PM2.5 in micrograms per cubic meter (mean PM2.5); and 3) total number of days with maximum 8-hour average ozone concentrations greater than the NAAQS (ozone days). The water-quality measure compared the annual mean concentration for a community water system (CWS) to the maximum contaminant level (MCL) defined by EPA for 10 contaminants: arsenic, atrazine, di(2-ethylhexyl) phthalate (DEHP), haloacetic acids (HAA5), nitrate, perchloroethene (PCE), radium, trichloroethene (TCE), total trihalomethanes (TTHM), and uranium. Findings are presented by urban-rural classification scheme: four metropolitan (large central metropolitan, large fringe metropolitan, medium metropolitan, and small metropolitan) and two nonmetropolitan (micropolitan and noncore) categories. Regression modeling was used to determine whether differences in the measures by urban-rural categories were statistically significant. Patterns for all three air-quality measures suggest that air quality improves as areas become more rural (or less urban). The mean total number of ozone days decreased from 47.54 days in large central metropolitan counties to 3.81 days in noncore counties, whereas the mean total number of PM2.5 days decreased from 11.21 in large central metropolitan counties to 0.95 in noncore counties. The mean average annual PM2.5 concentration decreased from 11.15 μg/m3 in large central metropolitan counties to 8.87 μg/m3 in noncore counties. Patterns for the water-quality measure suggest that water quality improves as areas become more urban (or less rural). Overall, 7% of CWSs reported at least one annual mean concentration greater than the MCL for all 10 contaminants combined. The percentage increased from 5.4% in large central metropolitan counties to 10% in noncore counties, a difference that was significant, adjusting for U.S. region, CWS size, water source, and potential spatial correlation. Similar results were found for two disinfection by-products, HAA5 and TTHM. Arsenic was the only other contaminant with a significant result. Medium metropolitan counties had 3.1% of CWSs reporting at least one annual mean greater than the MCL, compared with 2.4% in large central counties. Noncore (rural) counties experienced fewer unhealthy air-quality days than large central metropolitan counties, likely because of fewer air pollution sources in the noncore counties. All categories of counties had a mean annual average PM2.5 concentration lower than the EPA standard. Among all CWSs analyzed, the number reporting one or more annual mean contaminant concentrations greater the MCL was small. The water-quality measure suggests that water quality worsens as counties become more rural, in regards to all contaminants combined and for the two disinfection by-products individually. Although significant differences were found for the water-quality measure, the odds ratios were very small, making it difficult to determine whether these differences have a meaningful effect on public health. These differences might be a result of variations in water treatment practices in rural versus urban counties. Understanding the differences between rural and urban areas in air and water quality can help public health departments to identify, monitor, and prioritize potential environmental public health concerns and opportunities for action. These findings suggest a continued need to develop more geographically targeted, evidence-based interventions to prevent morbidity and mortality associated with poor air and water quality.


Building personal maps from GPS data.
In this article we discuss an assisted cognition information technology system that can learn personal maps customized for each user and infer his daily activities and movements from raw GPS data. The system uses discriminative and generative models for different parts of this task. A discriminative relational Markov network is used to extract significant places and label them; a generative dynamic Bayesian network is used to learn transportation routines, and infer goals and potential user errors at real time. We focus on the basic structures of the models and briefly discuss the inference and learning techniques. Experiments show that our system is able to accurately extract and label places, predict the goals of a person, and recognize situations in which the user makes mistakes, such as taking a wrong bus.


In vitro testicular toxicity models: opportunities for advancement via biomedical engineering techniques.
To address the pressing need for better in vitro testicular toxicity models, a workshop sponsored by the International Life Sciences Institute (ILSI), the Health and Environmental Science Institute (HESI), and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), was held at the Mt. Washington Conference Center in Baltimore, MD, USA on October 26-27, 2011. At this workshop, experts in testis physiology, toxicology, and tissue engineering discussed approaches for creating improved in vitro environments that would be more conducive to maintaining spermatogenesis and steroidogenesis and could provide more predictive models for testicular toxicity testing. This workshop report is intended to provide scientists with a broad overview of relevant testicular toxicity literature and to suggest opportunities where bioengineering principles and techniques could be used to build improved in vitro testicular models for safety evaluation. Tissue engineering techniques could, conceivably, be immediately implemented to improve existing models. However, it is likely that in vitro testis models that use single or multiple cell types will be needed to address such endpoints as accurate prediction of chemically induced testicular toxicity in humans, elucidation of mechanisms of toxicity, and identification of possible biomarkers of testicular toxicity.


Iron in relation to gastric cancer in the Alpha-tocopherol, Beta-carotene Cancer Prevention Study.
Iron is an essential micronutrient that can have carcinogenic effects when at high or low concentrations. Previous studies of iron in relation to gastric cancer have not assessed subtype-specific relationships. We used the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC). We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 nonspecified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity, and C-reactive protein. Total iron-binding capacity (TIBC) and transferrin saturation were estimated from these metrics. Dietary iron exposures were estimated from a food frequency questionnaire. Multivariable logistic regression was used for analysis. Serum iron metrics were not associated with GCC, except for a potential "n"-shaped relationship with TIBC (global P = 0.038). GNCC was inversely associated with serum ferritin (global P = 0.024), serum iron (global P = 0.060) and, possibly, transferrin saturation. TIBC appeared to share a "u"-shaped relationship with GNCC (global P = 0.033). Dietary iron exposures were not associated with either subsite. Adjustment for Helicobacter pylori and gastric atrophy had little effect on observed associations. We found little evidence for the involvement of iron exposure in the pathogenesis of GCC. GNCC was associated with an iron profile similar to that of iron deficiency. Our findings indicate that inverse associations between iron metrics and gastric cancer are driven by associations with GNCC. Further elucidation of potential mechanisms is warranted.


Phylogeny of benthic Phyllodocidae (Polychaeta) based on morphological and molecular data.
A combined molecular (18S rDNA, 28S rDNA, 16S rDNA and COI) and morphological analysis of the benthic phyllodocids is presented for the first time. Nineteen phyllodocids and two outgroup taxa are assessed using parsimony, maximum likelihood and Bayesian analyses. We demonstrate high degrees in homoplasy in the traditionally used morphological phyllodocid characters, and show that all the three current subfamilies Phyllodocinae, Eteoninae and Notophyllinae are non-monophyletic. The genera Eulalia, Eumida, Protomystides, Pseudomystides, Pterocirrus and Sige form a well-supported group, as does Mystides and Nereiphylla. Another clade with strong support includes Eteone and Paranaitis, although with Eteone nested within a paraphyletic Paranaitis. The relationship between these two taxa indicate that the unusual arrangement of modified cirri on the first segments in Eteone is due to a fusion of segment 1 and 2 where the cirri of segment 1 have been reduced. Eulalia is non-monophyletic and should be split, minimally into two groups. Our results are ambiguous regarding the ancestral phyllodocid condition of absence-presence of median antenna or nuchal papilla and uniramous or biramous parapodia, but shows that the absence of cirri on segment 3 (previously an apomorphy, for e.g., Mystides, Pseudomystides and Hesionura) is maximally homoplastic.


Creating nanopatterns of His-tagged proteins on surfaces by nanoimprint lithography using specific NiNTA-histidine interactions.
Directed assembly of the DsRed FT protein is demonstrated on self-assembled monolayers (SAMs) on silicon substrates patterned by nanoimprint lithography. Initially, the DsRed protein is attached using electrostatic interactions on both topographical (polymer) templates with an amino functionalization and on chemically patterned (flat) substrates. In a second experiment, a patterned NiNTA SAM is used in order to attach the DsRed FT protein via supramolecular interactions, taking advantage of the histidine functionalization of the DsRed FT protein. The NTA SAM is formed on silicon oxide using a multistep covalent process. Patterning of the NTA SAM is performed using nanoimprint lithography. The DsRed FT protein is attached on the patterned NTA layer after treating this with a Ni(II) solution. Moreover, the histidine-NiNTA binding may be reversed by removing the Ni using EDTA or by competition using imidazole. The regeneration and reuse of the substrate by subsequently attaching and removing two different histidine-functionalized proteins from the patterned NTA is shown by fluorescence microscopy.


Quantum dot loaded immunomicelles for tumor imaging.
Optical imaging is a promising method for the detection of tumors in animals, with speed and minimal invasiveness. We have previously developed a lipid coated quantum dot system that doubles the fluorescence of PEG-grafted quantum dots at half the dose. Here, we describe a tumor-targeted near infrared imaging agent composed of cancer-specific monoclonal anti-nucleosome antibody 2C5, coupled to quantum dot (QD)-containing polymeric micelles, prepared from a polyethylene glycol/phosphatidylethanolamine (PEG-PE) conjugate. Its production is simple and involves no special equipment. Its imaging potential is great since the fluorescence intensity in the tumor is twofold that of non-targeted QD-loaded PEG-PE micelles at one hour after injection. Para-nitrophenol-containing (5%) PEG-PE quantum dot micelles were produced by the thin layer method. Following hydration, 2C5 antibody was attached to the PEG-PE micelles and the QD-micelles were purified using dialysis. 4T1 breast tumors were inoculated subcutaneously in the flank of the animals. A lung pseudometastatic B16F10 melanoma model was developed using tail vein injection. The contrast agents were injected via the tail vein and mice were depilated, anesthetized and imaged on a Kodak Image Station. Images were taken at one, two, and four hours and analyzed using a methodology that produces normalized signal-to-noise data. This allowed for the comparison between different subjects and time points. For the pseudometastatic model, lungs were removed and imaged ex vivo at one and twenty four hours. The contrast agent signal intensity at the tumor was double that of the passively targeted QD-micelles with equally fast and sharply contrasted images. With the side views of the animals only tumor is visible, while in the dorsal view internal organs including liver and kidney are visible. Ex vivo results demonstrated that the agent detects melanoma nodes in a lung pseudometastatic model after a 24 hours wash-out period, while at one hour, only a uniform signal is detected. The targeted agent produces ultrabright tumor images and double the fluorescence intensity, as rapidly and at the same low dose as the passively targeted agents. It represents a development that may potentially serve to enhance early detection for metastases.


Prehistoric contacts over the Straits of Gibraltar indicated by genetic analysis of Iberian Bronze Age cattle.
The geographic situation of the Iberian Peninsula makes it a natural link between Europe and North Africa. However, it is a matter of debate to what extent African influences via the Straits Gibraltar have affected Iberia's prehistoric development. Because early African pastoralist communities were dedicated to cattle breeding, a possible means to detect prehistoric African-Iberian contacts might be to analyze the origin of cattle breeds on the Iberian Peninsula. Some contemporary Iberian cattle breeds show a mtDNA haplotype, T1, that is characteristic to African breeds, generally explained as being the result of the Muslim expansion of the 8th century A.D., and of modern imports. To test a possible earlier African influence, we analyzed mtDNA of Bronze Age cattle from the Portalón cave at the Atapuerca site in northern Spain. Although the majority of samples showed the haplotype T3 that dominates among European breeds of today, the T1 haplotype was found in one specimen radiocarbon dated 1800 calibrated years B.C. Accepting T1 as being of African origin, this result indicates prehistoric African-Iberian contacts and lends support to archaeological finds linking early African and Iberian cultures. We also found a wild ox haplotype in the Iberian Bronze Age sample, reflecting local hybridization or backcrossing or that aurochs were hunted by these farming cultures.


Beyond the clinic: improving child health through evidence-based community development.
Promoting child wellbeing necessarily goes beyond the clinic as risks to child health and development are embedded in the social and physical environmental conditions in which children live. Pediatricians play a vital role in promoting the health of children in the communities they serve and can maximize their impact by advocating for and supporting efficacious, evidence-based strategies in their communities. To provide a succinct guide for community pediatric efforts to advance the wellbeing of all children and particularly disadvantaged children in a community, we conducted a theory-driven and structured narrative review to synthesize published systematic and meta-analytic reviews of policy-relevant, local-level strategies addressing potent and malleable influences on child health and development. An exhaustive list of policy-relevant, local-level strategies for improving child health was used to conduct a comprehensive search of recent (1990-2012), English language peer-reviewed published meta-analyses and systematic reviews in the 10 core databases of scientific literature. Our review of the literature encompassed six key conceptual domains of intervention foci, including distal influences of child health (i.e., income and resources, social cohesion, and physical environment) and proximal influences (i.e., family, school and peer). We examined intervention effects on four key domains of child health and development: cognitive development, social and emotional competence, psychological and behavioral wellbeing, and physical health. Published reviews were identified for 98 distinct policy-relevant community interventions, evaluated across 288 outcomes. We classified 46 strategies as meeting scientific criteria for efficacy by having consistent, positive outcomes from high-quality trials (e.g., tenant-based rental assistance, neighborhood watch programs, urban design and land use policies, access to quality childcare services, class size reductions, after-school programs that promote personal/social skills). Another 21 strategies were classified as having consistent evidence of positive outcomes from high-quality observational studies only, while 28 strategies had insufficient evidence available to assess their effectiveness based on published reviews. We did not limit the review to studies conducted in the United States, but the vast majority of them were U.S.-based, and the results therefore are most applicable to the U.S. context. Based on our synthesis of published literature on community development strategies, we provide an illustration combining a comprehensive set of evidence-based strategies to promote child health and development across a wide-range of child health outcomes.


The lymphocyte-specific protein tyrosine kinase p56lck is hyperphosphorylated on serine and tyrosine residues within minutes after activation via T cell receptor or CD2.
Human T cells can be activated and induced to proliferate through either the antigen-specific receptor complex (TcR-CD3) or the CD2 surface molecule. Following stimulation, both serine and tyrosine phosphorylation of cellular protein have been demonstrated to occur. p56lck, a protein tyrosine kinase associated to the inner face of the plasma membrane, is almost exclusively expressed in lymphoid cells, especially T cells. Within minutes after activation of a human T cell-derived line (Jurkat) via stimulation of either the TcR-CD3 complex or the CD2 glycoprotein, we observed a hyperphorphosylation of p56lck. A concomitant shift to a higher molecular weight in sodium dodecyl sulfate-polyacrylamide gel was also observed. Similar changes were obtained with phorbol 12-myristate 13-acetate. Tryptic phosphopeptide analysis of the hyperphosphorylated form of p56lck yielded new phosphorylated sites in serine residues and an increased tyrosine phosphorylation. These results suggest that p56lck may be intimately connected to the signaling pathway in T cell activation.


Red blood cell membrane-coated upconversion nanoparticles for pretargeted multimodality imaging of triple-negative breast cancer.
Upconversion nanoparticles (UCNPs) have been widely employed for tumor imaging using magnetic resonance imaging (MRI) and upconversion luminescence (UCL) imaging. The short blood clearance time and immunogenicity of UCNPs have limited their further application in vivo. We have designed UCNPs camouflaged with an exterior red blood cell (RBC) membrane coating (RBC-UCNPs) to solve these problems. Moreover, because of some intrinsic disadvantages of MRI and UCL imaging, we investigated the use of pretargeted RBC-UCNPs for positron-emission tomography (PET) imaging to obtain more comprehensive information. Our data showed that RBC-UCNPs retained the immunity feature from the source cells and the superior optical and chemical features from the pristine UCNP cores. The tumor-targeting ability of RBC-UCNPs was enhanced by binding 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[folate(polyethylene glycol)-2000] (DSPE-PEG-FA) molecules onto the cell membranes. PET imaging with short half-life radionuclides to visualize the RBC-UCNPs was successfully realized by a combination of pre-targeting and in vivo click chemistry. Blood chemistry, hematology, and histologic analysis suggested good in vivo biocompatibility of the RBC-UCNPs. Our method provides a new potential biomedical application of biomimetic nanoparticles.


The impact of various backboard configurations on compression stiffness in a manikin study of CPR.
When performing cardiopulmonary resuscitation (CPR) it is important that adequate back support is given to the patient in order to allow the medical practitioner to produce an appropriate technique during chest compression (CC). The current study investigates how backboard configuration (i.e., orientation and size) impact compression stiffness during CPR using a torso CPR training manikin. The effect of backboard size on CC performance during CPR was found to be significant with the 94.8% larger backboard producing an increase in compression stiffness of as much as 62.7% relative to the smaller backboard. The impact of backboard orientation was also found to be important with a longitudinal orientation producing an increase in compression stiffness of as much as 60.3% relative to a latitudinal orientation. Backboard configuration should be considered by clinicians when trying to achieve optimal CC performance during CPR in hospital settings.


Validation of a simple method for measuring cranial deformities (plagiocephalometry).
Craniofacial measuring is essential for diagnosis or evaluation of growth and therapies. Skull deformities in children are mainly caused by craniosynostosis or by external pressure in positional skull deformations. Traditional anthropometry does not sufficiently analyze craniofacial shape. In computed tomography (CT) scanning, radiation loads are considerable. Both CT and magnetic resonance imaging (MRI) scanning require anaesthesia in children for accurate imaging, due to their long acquisition time. This makes CT and MRI unsuitable for long term follow-up of pediatric patients unless there is a compelling reason. Other noninvasive three-dimensional (3D) surface scanners still have limited practical use. van Vlimmeren et al presented plagiocephalometry (PCM) as a simple and versatile instrument to quantify skull deformities with high intrarater and interrater reliability, but no comparison was made with the actual skull shape. At the Erasmus University Medical Center Rotterdam, Sophia Children's Hospital PCM was compared to 3D-CT scanning in 21 children with craniosynostosis early in life. The PCM ring proved to fit closely to the skin with mean differences less than 1 mm (P < 0.05). The shape of the PCM ring was not significantly changed when taken off the head (P > 0.05). Finally, no significant differences are shown between measurements on the skull (CT-scan) and PCM ring off the head (P > 0.05). This study proves that PCM is a reliable method for analysis of skull deformities. The measurements are in agreement with 3D-CT scanning as golden standard. Although only 2-dimensional measurements are performed by PCM, the combination of simplicity, reliability, and validity make it a promising tool for daily practice.


WHO guidelines for severe malnutrition: are they feasible in rural African hospitals?
To assess the feasibility of implementing and sustaining the WHO guidelines for inpatient management of severe malnutrition in under-resourced rural South African hospitals, and to identify any constraints. Three 2-day training workshops were held in 1998, followed by monthly 1-day visits for 5 months, ending in March 1999, in two rural district hospitals with limited resources in Eastern Cape Province, South Africa. A 12-month observational study was conducted from April 2000 to April 2001 in Mary Theresa and Sipetu hospitals (Eastern Cape Province, South Africa), including 1011 child-hours of observation on the wards, medical record reviews, interviews with carers and staff, and inventories of essential supplies. All admissions (n = 193) for severe malnutrition to the two hospitals were studied. The main outcomes were the extent to which the 10 steps for routine care of severely malnourished children were implemented, proficiency of performance and constraining factors. The hospitals made the changes required in clinical and dietary management, but the tasks were not always performed fully or with sufficient care. Play and stimulation and an effective system of follow-up were not implemented. Doctors' poor knowledge, nurses' inattentiveness and insufficient interaction with carers were constraints to optimal management. The underlying factors were inadequate undergraduate training, understaffing, high doctor turnover and low morale. Guidelines for severe malnutrition are largely feasible but training workshops are insufficient to achieve optimal management as staff turnover and an unsupportive health system erode the gains made and doctors treat cases without having being trained. Medical and nursing curricula in Africa must include treatment of severe malnutrition.


Polypill: the evidence and the promise.
In spite of great scientific advances, cardiovascular disease is the commonest cause of death worldwide and current cardiovascular prevention strategies fail to achieve the full potential of risk modification. A large amount of evidence supports the use of pharmacological treatments both in primary and secondary prevention and it was hypothesized that a fixed-dose combination of such drugs, a 'polypill', may greatly simplify and improve current prevention strategies. Several polypill formulations have been developed and a recent trial demonstrated the short-term feasibility, safety and efficacy (in reducing risk factor levels) of a polypill in individuals at moderate risk. Many challenges remain and studies are underway, which will address questions related to formulation of polypill(s), the long-term safety and tolerability, the efficacy in reducing risk factor levels and cardiovascular events, physician, patient and societal acceptability, adherence, regulatory requirements, cost and impact on lifestyle habits. Theoretical models suggest that a polypill containing low-dose aspirin, three blood pressure-lowering drugs at half dose and a potent statin, administered to a large proportion of the population at risk for cardiovascular events, could reduce ischemic heart disease and strokes by over 80%. The feasibility of this approach has recently been shown in a clinical trial and ongoing studies will define whether the postulated benefits of the polypill will be observed.


30+ years of media analysis of relevance to chronic disease: a scoping review.
Chronic, non-communicable diseases are a significant public health priority, requiring action at individual, community and population levels, and public and political will for such action. Exposure to media, including news, entertainment, and advertising media, is likely to influence both individual behaviours, and attitudes towards preventive actions at the population level. In recent years there has been a proliferation of research exploring how chronic diseases and their risk factors are portrayed across various forms of media. This scoping review aims to map the literature in this area to identify key themes, gaps, and opportunities for future research in this area. We searched three databases (Medline, PsycINFO and Global Health) in July 2016 and identified 499 original research articles meeting inclusion criteria: original research article, published in English, focusing on media representations of chronic disease (including how issues are framed in media, impact or effect of media representations, and factors that influence media representations). We extracted key data from included articles and examined the health topics, media channels and methods of included studies, and synthesised key themes across studies. Our findings show that research on media portrayals of chronic disease increased substantially between 1985 and 2016. Smoking and nutrition were the most frequent health topics, and television and print were the most common forms of media examined, although, as expected, research on online and social media channels has increased in recent years. The majority of studies focused on the amount and type of media coverage, including how issues are framed, typically using content analysis approaches. In comparison, there was much less research on the influences on and consequences of media coverage related to chronic disease, suggesting an important direction for future work. The results highlight key themes across media research of relevance to chronic disease. More in-depth syntheses of studies within the identified themes will allow us to draw out the key patterns and learnings across the literature.


Inter-epidemic transmission of Rift Valley fever in livestock in the Kilombero River Valley, Tanzania: a cross-sectional survey.
In recent years, evidence of Rift Valley fever (RVF) transmission during inter-epidemic periods in parts of Africa has increasingly been reported. The inter-epidemic transmissions generally pass undetected where there is no surveillance in the livestock or human populations. We studied the presence of and the determinants for inter-epidemic RVF transmission in an area experiencing annual flooding in southern Tanzania. A cross-sectional sero-survey was conducted in randomly selected cattle, sheep and goats in the Kilombero river valley from May to August 2011, approximately four years after the 2006/07 RVF outbreak in Tanzania. The exposure status to RVF virus (RVFV) was determined using two commercial ELISA kits, detecting IgM and IgG antibodies in serum. Information about determinants was obtained through structured interviews with herd owners. An overall seroprevalence of 11.3% (n = 1680) was recorded; 5.5% in animals born after the 2006/07 RVF outbreak and 22.7% in animals present during the outbreak. There was a linear increase in prevalence in the post-epidemic annual cohorts. Nine inhibition-ELISA positive samples were also positive for RVFV IgM antibodies indicating a recent infection. The spatial distribution of seroprevalence exhibited a few hotspots. The sex difference in seroprevalence in animals born after the previous epidemic was not significant (6.1% vs. 4.6% for females and males respectively, p = 0.158) whereas it was significant in animals present during the outbreak (26.0% vs. 7.8% for females and males respectively, p<0.001). Animals living >15 km from the flood plain were more likely to have antibodies than those living <5 km (OR 1.92; 95% CI 1.04-3.56). Species, breed, herd composition, grazing practices and altitude were not associated with seropositivity. These findings indicate post-epidemic transmission of RVFV in the study area. The linear increase in seroprevalence in the post-epidemic annual cohorts implies a constant exposure and presence of active foci transmission preceding the survey.


Improving the Quality of Positive Datasets for the Establishment of Machine Learning Models for pre-microRNA Detection.
MicroRNAs (miRNAs) are involved in the post-transcriptional regulation of protein abundance and thus have a great impact on the resulting phenotype. It is, therefore, no wonder that they have been implicated in many diseases ranging from virus infections to cancer. This impact on the phenotype leads to a great interest in establishing the miRNAs of an organism. Experimental methods are complicated which led to the development of computational methods for pre-miRNA detection. Such methods generally employ machine learning to establish models for the discrimination between miRNAs and other sequences. Positive training data for model establishment, for the most part, stems from miRBase, the miRNA registry. The quality of the entries in miRBase has been questioned, though. This unknown quality led to the development of filtering strategies in attempts to produce high quality positive datasets which can lead to a scarcity of positive data. To analyze the quality of filtered data we developed a machine learning model and found it is well able to establish data quality based on intrinsic measures. Additionally, we analyzed which features describing pre-miRNAs could discriminate between low and high quality data. Both models are applicable to data from miRBase and can be used for establishing high quality positive data. This will facilitate the development of better miRNA detection tools which will make the prediction of miRNAs in disease states more accurate. Finally, we applied both models to all miRBase data and provide the list of high quality hairpins.


The impact of therapeutic opioid agonists on driving-related psychomotor skills assessed by a driving simulator or an on-road driving task: A systematic review.
Driving cessation is associated with poor health-related outcomes. People with chronic diseases are often prescribed long-term opioid agonists that have the potential to impair driving. Studies evaluating the impact of opioids on driving-related psychomotor skills report contradictory results likely due to heterogeneous designs, assessment tools and study populations. A better understanding of the effects of regular therapeutic opioid agonists on driving can help to inform the balance between individual's independence and community safety. To identify the literature assessing the impact of regular therapeutic opioid agonists on driving-related psychomotor skills for people with chronic pain or chronic breathlessness. Systematic review reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis statement; PROSPERO Registration CRD42017055909. Six electronic databases and grey literature were systematically searched up to January, 2017. Inclusion criteria were as follows: (1) empirical studies reporting data on driving simulation, on-the-road driving tasks or driving outcomes; (2) people with chronic pain or chronic breathlessness; and (3) taking regular therapeutic opioid agonists. Critical appraisal used the National Institutes of Health's quality assessment tools. From 3809 records screened, three studies matched the inclusion criteria. All reported data on people with chronic non-malignant pain. No significant impact of regular therapeutic opioid agonists on people's driving-related psychomotor skills was reported. One study reported more intense pain significantly worsened driving performance. This systematic review does not identify impaired simulated driving performance when people take regular therapeutic opioid agonists for symptom control, although more prospective studies are needed.


Sprinting Biomechanics and Hamstring Injuries: Is There a Link? A Literature Review.
Hamstring strain injury (HSI) is a common and costly injury in many sports such as the various professional football codes. Most HSIs have been reported to occur during high intensity sprinting actions. This observation has led to the suggestion that a link between sprinting biomechanics and HSIs may exist. The aim of this literature review was to evaluate the available scientific evidence underpinning the potential link between sprinting biomechanics and HSIs. A structured search of the literature was completed followed by a risk of bias assessment. A total of eighteen studies were retrieved. Sixteen studies involved retrospective and/or prospective analyses, of which only three were judged to have a low risk of bias. Two other case studies captured data before and after an acute HSI. A range of biomechanical variables have been measured, including ground reaction forces, trunk and lower-limb joint angles, hip and knee joint moments and powers, hamstring muscle-tendon unit stretch, and surface electromyographic activity from various trunk and thigh muscles. Overall, current evidence was unable to provide a clear and nonconflicting perspective on the potential link between sprinting biomechanics and HSIs. Nevertheless, some interesting findings were revealed, which hopefully will stimulate future research on this topic.


Visually induced activity in human frontal motor areas during simple visuomotor performance.
Visuomotor tasks elicit neuronal activity in primate motor areas at relatively short latencies. Although this early activity embodies features of visual responses (short latency, stimulus-dependency), its sensory nature has been questioned. We investigated neural correlates of visuomotor performance in human motor areas using scalp and intracranial event-related potential measures. A simple visuomanual reaction-time task evoked early potentials at 133-145 ms post-stimulus which occurred much earlier than the motor potentials of the same region. The amplitude of the early potentials covaried with stimulus location and was independent of parameters of the motor response. Because of their timing, stimulus-dependency and characteristics of our behavioral task, the early potentials are suggested to reflect neuronal responses of sensory nature rather than processing related to pure motor aspects of the task.


Pre-dispensing of antivirals to high-risk individuals in an influenza pandemic.
We consider the net benefits of pre-dispensing antivirals to high-risk individuals during an influenza pandemic, where the measure of the benefit is the number of severe outcomes (such as deaths or hospitalizations) prevented by antivirals in the whole population. One potential benefit of pre-dispensing is that individuals to whom antivirals have been pre-dispensed may be able to initiate treatment earlier than if they had to wait to obtain and fill a prescription, reducing their risk of progression to severe disease. If this benefit exceeds the side effects of misuse for the category of individuals to whom antivirals were pre-dispensed, and if antiviral supply exceeds overall population demand (which appears relevant for several countries including US in the 2009 H1N1 pandemic), pre-dispensing a quantity of antivirals not exceeding the difference between supply and demand is always beneficial. In this study, we consider the net benefits of pre-dispensing antivirals under various scenarios, including demand exceeding supply, and derive mathematical conditions under which antiviral pre-dispensing is advantageous on balance. For individuals whose relative risk of severe outcome is high enough, such as immunosuppressed individuals (particularly children) and possibly individuals with neurological disorders, pre-dispensing is always beneficial at a given level of antiviral stockpile with modest assumptions on the relative benefit of early treatment by a pre-dispensed course, regardless of the overall population demand for antivirals during the course of an epidemic. Making additional assumptions on either the overall population demand for antivirals (which appear relevant for the 2009 H1N1 pandemic) or on the relative benefit of pre-dispensing would make pre-dispensing net beneficial with inclusion of a larger number of persons such as pregnant women and morbidly obese adults.


The effect of L-tyrosine on some anti-nociceptive and non-nociceptive actions of morphine in mice.
1. This work examines the effect of L-tyrosine on the antinociceptive and non-nociceptive actions of morphine in mice. The antinociceptive action was measured using the hot plate method, and the non-nociceptive actions included the effect on concentrations of glucose, cholesterol and triglycerides in serum or blood, and the effect on gastrointestinal transit time (GITT) and rectal temperature. 2. L-tyrosine (25, 50, 100 and 200 mg/kg), subcutaneously (s.c.) dose-dependently potentiated the antinociceptive action of morphine (5 mg/kg, s.c.). L-tyrosine alone did not produce significant antinociceptive action, nor did it affect any of the other non-nociceptive actions measured. 3. Acute administration of morphine (5, 10 and 20 mg/kg) produced dose-dependent increases in blood glucose concentration which were insignificantly potentiated by L-tyrosine (25-200 mg/kg) when given together with morphine. Morphine produced dose-dependent and significant decrease in serum triglycerides concentrations, an effect which was not influenced by L-tyrosine treatment. Serum cholesterol was not affected by treatment with morphine, either alone or when given with L-tyrosine. 4. Morphine produced dose-dependent and significant decreases in GITT which was not affected with L-tyrosine.


The role of volitional effort in the Bielschowsky head tilt test: a clinical and oculographic assessment.
To determine whether volitional effort on the part of the subject can influence the results of the Bielschowsky Head Tilt Test. Bielschowsky Head Tilt testing was performed in five normal subjects. Vertical amplitudes were measured with prism alternate cover testing when the head tilt was voluntary (volitionally maintained in a tilted position by the subject), forced (restrained in the tilted position by the examiner while the patient actively resisted) and active (restrained in a tilted position by the examiner with the subject actively trying to increase the tilt). Three-dimensional scleral search coil recordings were performed in three additional normal subjects using the same paradigm to determine the effect of volition on the torsional positions of the eyes. No vertical deviation of the eyes was detectable with prism alternate cover testing in any position of tilt, regardless of whether the tilt was voluntary, forced, or active. Volitional attempts to tilt the head were preceded by a transient ipsiversive torsional movement of the measured eye, which was quickly followed by a normal ocular counterroll. Following completion of the counterroll, the position of the eyes was constant for any position of head tilt, regardless of whether the tilt was forced, active, or voluntary. Anticipatory torsional movements of the eyes are evoked by an attempted volitional head movement in the roll plane and its associated innervation to the cervical musculature. However, these volitional movements do not alter the final torsional position of the eyes, which is a function of the degree of head tilt and the normal ocular counterroll. These anticipatory torsional movements do not influence the results of the Bielschowsky Head Tilt Test clinically by prism alternate cover testing.


Carotid plaque characteristics and disease activity in rheumatoid arthritis.
Carotid plaques (CP) are predictive of acute coronary syndrome in patients with rheumatoid arthritis (RA), suggesting that atherosclerotic plaques in these patients are vulnerable. The objective of our study was to characterize vulnerability of CP in patients with RA compared to a control population, and between RA patients with different levels of disease activity. Ultrasound examination of carotid arteries was performed in 152 patients with RA and 89 controls. CP echolucency was evaluated by the Gray-Scale Median (GSM) technique. Lower GSM values indicate higher vulnerability of plaques. CP characteristics were compared between RA patients with active disease and in remission, and between patients and controls. All analyses were performed with adjustment for confounding factors (sex, age, smoking, and blood pressure). Poisson regression analysis was used for count data, mixed modeling for GSM and area per plaque, and analysis of covariance for minimum GSM value per patient. Patients with RA more frequently had CP (median 2, range 0, 4) compared with controls (median 1, range 0, 3; p < 0.001), after adjustment for age and sex. Patients with active RA disease according to the Clinical Disease Activity Index (CDAI) had lower median GSM (p = 0.03), minimum GSM (p = 0.03), and a larger CP area (although the latter finding was not significant; p = 0.27), compared with patients with RA in remission. These findings were not confirmed for other disease measures (Simplified Disease Activity Index, Disease Activity Score-28, C-reactive protein, erythrocyte sedimentation rate). Patients with RA had more CP compared with controls and patients in CDAI remission, and controls had more stable CP than patients with active disease; these findings point to the importance of achieving remission in RA.


A flexible mixed-effect negative binomial regression model for detecting unusual increases in MRI lesion counts in individual multiple sclerosis patients.
We develop a new modeling approach to enhance a recently proposed method to detect increases of contrast-enhancing lesions (CELs) on repeated magnetic resonance imaging, which have been used as an indicator for potential adverse events in multiple sclerosis clinical trials. The method signals patients with unusual increases in CEL activity by estimating the probability of observing CEL counts as large as those observed on a patient's recent scans conditional on the patient's CEL counts on previous scans. This conditional probability index (CPI), computed based on a mixed-effect negative binomial regression model, can vary substantially depending on the choice of distribution for the patient-specific random effects. Therefore, we relax this parametric assumption to model the random effects with an infinite mixture of beta distributions, using the Dirichlet process, which effectively allows any form of distribution. To our knowledge, no previous literature considers a mixed-effect regression for longitudinal count variables where the random effect is modeled with a Dirichlet process mixture. As our inference is in the Bayesian framework, we adopt a meta-analytic approach to develop an informative prior based on previous clinical trials. This is particularly helpful at the early stages of trials when less data are available. Our enhanced method is illustrated with CEL data from 10 previous multiple sclerosis clinical trials. Our simulation study shows that our procedure estimates the CPI more accurately than parametric alternatives when the patient-specific random effect distribution is misspecified and that an informative prior improves the accuracy of the CPI estimates.


Immune Modulation and Treatment of Human Papilloma Virus-Related Warts with Energetics of Living Systems Acupuncture.
Background: Cutaneous warts are small skin lesions formed as a result of infection by the human papilloma virus (HPV). In the lesion, viral manipulation creates a microenvironment that favors virus survival and reproduction. Most lesions eventually regress, probably as a result of a Th1-mediated immune response. However, some warts fail to regress and become persistent. Objective: The efficacy of treatment of persistent HPV-caused warts with Energetics of Living Systems acupuncture and monitored immune system involvement was tested. Methods: Eighteen patients with persistent warts were recruited for the study; 9 received acupuncture treatment and 9 received placebo. Each patient was treated 4 times. Results: Clinical success was defined as total clearance of all lesions with no recurrence for 3 months. In the treatment group, clinical success was 36.6% versus 0% in the placebo group. In the treatment group, the level of interleukin (IL)-10 decreased. In a comparison of patients with cleared warts and overall patients with nonresponding warts, different expression levels of IL-8, IL-10, tumor necrosis factor-α, IL-6, and interferon-γ were found, although these differences were not always statistically significant. Trends of differences (not significant) were observed in leukocyte levels. Acupuncture eliminated persistent warts in some of the patients, along with inducing changes in immunologic parameters. Conclusions: Taking the clinical and immunologic outcomes together, clearance of persistent warts following acupuncture might be due to a shift toward a Th1 immune response, or an anti-inflammatory effect against the lesion-induced microenvironment.


Transient iron overload with bleomycin detectable iron in the plasma of patients with adult respiratory distress syndrome.
A retrospective study was conducted to evaluate iron status in plasma samples collected from five patients with the adult respiratory distress syndrome (ARDS) who had bleomycin detectable iron in at least one sample. Ten patients with ARDS with no evidence of bleomycin detectable iron and 10 healthy individuals served as controls. Evidence of iron overload was established by measuring the percentage saturation of plasma transferrin. In each case the bleomycin assay for redox active, chelatable iron was used to measure plasma levels of non-transferrin bound iron in the low micromolar range; assays for total plasma iron and transferrin were performed to establish a diagnosis of transient iron overload. The effect of this on the ability of transferrin to act as a plasma antioxidant was assessed using two different assay systems. The five patients with evidence of transient iron overload (mortality 4/5) represented 33% of the total population of patients with ARDS (mortality 5/10) managed by the unit during the study period. All had low molecular mass iron detectable in their plasma and had clinical and biochemical evidence of multiorgan system failure as well as liver impairment. Compared with the ARDS and normal control populations, transferrin and albumin levels were low and the former failed to act as a plasma antioxidant in preventing free radical mediated damage to detector molecules. Patients with ARDS are thought to be under severe oxidative stress from their disease and from treatment with high inspired oxygen concentrations. A subgroup of patients with ARDS has been identified who displayed evidence of transient iron overload as a result of which their plasma iron binding antioxidant protection was greatly compromised. This finding must be considered a serious additional risk factor for oxidative stress.


A liposomal drug platform overrides peptide ligand targeting to a cancer biomarker, irrespective of ligand affinity or density.
One method for improving cancer treatment is the use of nanoparticle drugs functionalized with targeting ligands that recognize receptors expressed selectively by tumor cells. In theory such targeting ligands should specifically deliver the nanoparticle drug to the tumor, increasing drug concentration in the tumor and delivering the drug to its site of action within the tumor tissue. However, the leaky vasculature of tumors combined with a poor lymphatic system allows the passive accumulation, and subsequent retention, of nanosized materials in tumors. Furthermore, a large nanoparticle size may impede tumor penetration. As such, the role of active targeting in nanoparticle delivery is controversial, and it is difficult to predict how a targeted nanoparticle drug will behave in vivo. Here we report in vivo studies for αvβ6-specific H2009.1 peptide targeted liposomal doxorubicin, which increased liposomal delivery and toxicity to lung cancer cells in vitro. We systematically varied ligand affinity, ligand density, ligand stability, liposome dosage, and tumor models to assess the role of active targeting of liposomes to αvβ6. In direct contrast to the in vitro results, we demonstrate no difference in in vivo targeting or efficacy for H2009.1 tetrameric peptide liposomal doxorubicin, compared to control peptide and no peptide liposomes. Examining liposome accumulation and distribution within the tumor demonstrates that the liposome, and not the H2009.1 peptide, drives tumor accumulation, and that both targeted H2009.1 and untargeted liposomes remain in perivascular regions, with little tumor penetration. Thus H2009.1 targeted liposomes fail to improve drug efficacy because the liposome drug platform prevents the H2009.1 peptide from both actively targeting the tumor and binding to tumor cells throughout the tumor tissue. Therefore, using a high affinity and high specificity ligand targeting an over-expressed tumor biomarker does not guarantee enhanced efficacy of a liposomal drug. These results highlight the complexity of in vivo targeting.


Talking in Fury: The Cortico-Subcortical Network Underlying Angry Vocalizations.
Although the neural basis for the perception of vocal emotions has been described extensively, the neural basis for the expression of vocal emotions is almost unknown. Here, we asked participants both to repeat and to express high-arousing angry vocalizations to command (i.e., evoked expressions). First, repeated expressions elicited activity in the left middle superior temporal gyrus (STG), pointing to a short auditory memory trace for the repetition of vocal expressions. Evoked expressions activated the left hippocampus, suggesting the retrieval of long-term stored scripts. Secondly, angry compared with neutral expressions elicited activity in the inferior frontal cortex IFC and the dorsal basal ganglia (BG), specifically during evoked expressions. Angry expressions also activated the amygdala and anterior cingulate cortex (ACC), and the latter correlated with pupil size as an indicator of bodily arousal during emotional output behavior. Though uncorrelated, both ACC activity and pupil diameter were also increased during repetition trials indicating increased control demands during the more constraint production type of precisely repeating prosodic intonations. Finally, different acoustic measures of angry expressions were associated with activity in the left STG, bilateral inferior frontal gyrus, and dorsal BG.


The preferential accumulation of heavy metals in different tissues following frequent respiratory exposure to PM2.5 in rats.
This study aimed to explore the pattern of accumulation of some of main heavy metals in blood and various organs of rats after exposed to the atmospheric fine particulate matter (PM2.5). Rats were randomly divided into control and three treatment groups (tracheal perfusion with 10 mg/kg, 20 mg/kg and 40 mg/kg of PM2.5 suspension liquid, respectively). Whole blood and the lung, liver, kidney, and cerebral cortex were harvested after rats were treated and sacrificed. The used heavy metals were detected using inductively coupled plasma-mass spectrometry (ICP-MS) instrument. As results, Lead was increased in the liver, lung and cerebral cortex and the level of manganese was significantly elevated in the liver and cerebral cortex in PM2.5 treated rats. Besides, arsenic was prominently enriched both in cerebral cortex and in blood, and so did the aluminum in the cerebral cortex and the copper in the liver. However, cadmium, chromium and nickel have shown no difference between the control group and the three PM2.5 treated groups. Following the exposure of PM2.5, different heavy metals are preferentially accumulated in different body tissues.


Republished article: The impact of diabetic retinopathy: understanding the patient's perspective.
Understanding the impact of a condition from the patient's perspective is important, and different types of patient-reported outcomes or instruments are available to help with this. This review article summarises the current evidence on the impact of diabetic retinopathy (DR) and its associated vision impairment on patient-reported outcomes. We have included research that has used a range of outcome measures to assess the impact of DR on generic health-related quality of life, utility, vision-functioning and vision-specific quality of life. This review also offers clarification on frequently misused psychometric terminologies to help clinicians and researchers better understand the literature associated with patient-reported outcome research. Overall, the evidence suggests that DR, particularly in its vision-threatening stages, has a substantial, negative impact on the patient. However, our understanding of the impact of DR is currently restricted due to limitations inherent in currently available patient-reported outcome measures. We conclude by discussing potential directions for future research in this area, such as item banking and computer adaptive testing.


Mortality and socioeconomic status in adults with childhood onset GH deficiency (GHD) is highly dependent on the primary cause of GHD.
Childhood onset GH deficiency (CO-GHD) is associated with increased morbidity and mortality; however, the patients' socioeconomic profile as adults is not fully known. Register study using Danish nationwide registries. Two hundred and sixty GHD males and 156 GHD females and 25,358 male and 15,110 female controls were included. Information was obtained concerning cohabitation, parenthood, education, income, retirement, convictions, and death. Income was analyzed using conditional logistic regression, and other outcomes were analyzed using Cox regression. Subgroups of GHD patients with malignant tumors, craniopharyngioma, idiopathic GHD, and others were investigated separately. Both male and female GHD patients had a significantly worse outcome on all studied socioeconomic parameters. Fewer GHD patients lived in partnerships and entered them later (male hazard ratio (HR): 0.31; female HR: 0.33), had fewer parenthoods (male HR: 0.26; female HR: 0.26), lower educational level (male HR: 0.58; female HR: 0.48), lower income, higher risk of retirement (male HR: 13.4; female HR: 24.2), and fewer convictions (male HR: 0.67; female HR: 0.49). Mortality was increased (male HR: 10.7; female HR: 21.4). Adjusted for marital and educational status, male HR of death was 5.2 and female HR 10.5. Patients with idiopathic GHD had a socioeconomic profile similar to controls. The primary causes of CO-GHD and concomitant diseases severely impair socioeconomic conditions and impact mortality; only the subgroup of patients with idiopathic GHD conditions was similar to the background population.


C9orf72 intermediate expansions of 24-30 repeats are associated with ALS.
The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population. In most people, the repeat length is 2, but in people with ALS, hundreds to thousands of repeats may be observed. A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size, and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. We investigated the association of this intermediate repeat with ALS by performing a meta-analysis of four previously published studies and a new British/Alzheimer's Disease Neuroimaging Initiative dataset of 1295 cases and 613 controls. The final dataset comprised 5071 cases and 3747 controls. Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size (random-effects model OR = 4.2, 95% CI = 1.23-14.35, p-value = 0.02). Furthermore, we showed a different frequency of the repeat between the northern and southern European populations (Fisher's exact test p-value = 5 × 10- 3). Our findings provide evidence for the association between intermediate repeats and ALS (p-value = 2 × 10- 4) with direct relevance for research and clinical practice by showing that an expansion of 24 or more repeats should be considered pathogenic.


The Combination Of Weak Expression Of PRDX4 And Very High MIB-1 Labelling Index Independently Predicts Shorter Disease-free Survival In Stage I Lung Adenocarcinoma.
Background: Oxidative stress plays pivotal roles in the progression of lung adenocarcinoma (LUAD) through cell signaling related closely to cancer growth. We previously reported that peroxiredoxin 4 (PRDX4), a secretory-type antioxidant enzyme, can protect against the development of various diseases, including potential malignancies. Since many patients with early-stage LUAD develop recurrence, even after curative complete resection, we investigated the association of the PRDX4 expression with the clinicopathological features and recurrence/prognosis using post-surgical samples of stage I-LUAD. Methods: The expression of PRDX4 and MIB-1, a widely accepted Ki67 protein, was immunohistochemically analysed in 206 paraffin-embedded tumour specimens of patients with stage I-LUAD. The PRDX4 expression was considered to be weak when less than 25% of the adenocarcinoma cells showed positive staining. Results: A weak PRDX4+ expression demonstrated a significantly close relationship with pathologically poor differentiation, highly invasive characteristics and recurrence. The decrease in PRDX4-positivity potentially induced cell growth in LUAD, which was correlated significantly with a very high MIB-1 labelling index (≥17.3%). Univariate/multivariate analyses revealed that the subjects with both weak PRDX4+ expression and a very high MIB-1 index had significantly worse disease-free survival rates than other subjects. Conclusions: The combination of weak PRDX4 expression and a very high MIB-1 index can predict high proliferating activity and recurrence with a potential poor prognosis, especially in post-operative stage I-LUAD patients.


Using public opinion to serve journalistic narratives: Rethinking vox pops and live two-way reporting in five UK election campaigns (2009-2017).
The news media are often accused of reporting politics in a too narrow and consensual way, excluding certain perspectives and issues that might better reflect the public's agenda. This study lends weight to this argument by not only demonstrating the party political focus of UK election coverage but also in the misleading way public opinion was, at times, represented. Analysing 6647 items and/or stories in the largest ever content analysis study of 4613 sources across five first- and second-order election campaigns in the United Kingdom, it comprehensively tracks how citizens and journalists appear in television news, as well as developing a finely grained, qualitative assessment of how public opinion was represented during the 2017 election campaign. Overall, the study found that political parties received the most amount of airtime, but in some election campaigns members of the public appeared in coverage more often than politicians. However, they were mostly granted limited airtime to articulate their views in vox pops. During the 2017 election campaign, the study found the editorial construction of public opinion in vox pops and live journalistic two-ways was shaped by a relatively narrow set of assumptions made by political journalists about the public's ideological views rather than consulting more objective measures of public opinion. So, for example, voters were portrayed as favouring more right- than left-wing policies despite evidence to the contrary. The use of citizens as sources is theorised as serving the pre-conceived narratives of journalists rather than reflecting a representative picture of public opinion. The study reinforces and advances academic debates about journalists and citizen-source interactions. More accurately engaging with people's concerns, it is concluded, will help move broadcasters beyond the narrow set of assumptions that typically serve their narratives of political coverage.


Berry fruits: compositional elements, biochemical activities, and the impact of their intake on human health, performance, and disease.
An overwhelming body of research has now firmly established that the dietary intake of berry fruits has a positive and profound impact on human health, performance, and disease. Berry fruits, which are commercially cultivated and commonly consumed in fresh and processed forms in North America, include blackberry ( Rubus spp.), black raspberry ( Rubus occidentalis), blueberry ( Vaccinium corymbosum), cranberry (i.e., the American cranberry, Vaccinium macrocarpon, distinct from the European cranberry, V. oxycoccus), red raspberry ( Rubus idaeus) and strawberry ( Fragaria x ananassa). Other berry fruits, which are lesser known but consumed in the traditional diets of North American tribal communities, include chokecherry ( Prunus virginiana), highbush cranberry ( Viburnum trilobum), serviceberry ( Amelanchier alnifolia), and silver buffaloberry ( Shepherdia argentea). In addition, berry fruits such as arctic bramble ( Rubus articus), bilberries ( Vaccinuim myrtillus; also known as bog whortleberries), black currant ( Ribes nigrum), boysenberries ( Rubus spp.), cloudberries ( Rubus chamaemorus), crowberries ( Empetrum nigrum, E. hermaphroditum), elderberries ( Sambucus spp.), gooseberry ( Ribes uva-crispa), lingonberries ( Vaccinium vitis-idaea), loganberry ( Rubus loganobaccus), marionberries ( Rubus spp.), Rowan berries ( Sorbus spp.), and sea buckthorn ( Hippophae rhamnoides), are also popularly consumed in other parts of the world. Recently, there has also been a surge in the consumption of exotic "berry-type" fruits such as the pomegranate ( Punica granatum), goji berries ( Lycium barbarum; also known as wolfberry), mangosteen ( Garcinia mangostana), the Brazilian açaí berry ( Euterpe oleraceae), and the Chilean maqui berry ( Aristotelia chilensis). Given the wide consumption of berry fruits and their potential impact on human health and disease, conferences and symposia that target the latest scientific research (and, of equal importance, the dissemination of this information to the general public), on the chemistry and biological and physiological functions of these "superfoods" are necessary.


How many dinosaur species were there? Fossil bias and true richness estimated using a Poisson sampling model.
The fossil record is a rich source of information about biological diversity in the past. However, the fossil record is not only incomplete but has also inherent biases due to geological, physical, chemical and biological factors. Our knowledge of past life is also biased because of differences in academic and amateur interests and sampling efforts. As a result, not all individuals or species that lived in the past are equally likely to be discovered at any point in time or space. To reconstruct temporal dynamics of diversity using the fossil record, biased sampling must be explicitly taken into account. Here, we introduce an approach that uses the variation in the number of times each species is observed in the fossil record to estimate both sampling bias and true richness. We term our technique TRiPS (True Richness estimated using a Poisson Sampling model) and explore its robustness to violation of its assumptions via simulations. We then venture to estimate sampling bias and absolute species richness of dinosaurs in the geological stages of the Mesozoic. Using TRiPS, we estimate that 1936 (1543-2468) species of dinosaurs roamed the Earth during the Mesozoic. We also present improved estimates of species richness trajectories of the three major dinosaur clades: the sauropodomorphs, ornithischians and theropods, casting doubt on the Jurassic-Cretaceous extinction event and demonstrating that all dinosaur groups are subject to considerable sampling bias throughout the Mesozoic.


Toward best-practice post-disaster mental health promotion for children: Sri Lanka.
There is a pressing need for low-cost intervention models to promote mental health among children in the wake of natural disasters. This article describes an evaluation of one such model: the Happy/Sad Letter Box (HSLB) Project, a mental health promotion intervention designed to minimize trauma in children, resulting from the Indian Ocean tsunami of 26 December 2004. The HSLB Project was implemented in 68 schools in Sri Lanka's Hambantota District from April 2005 forward. Methods included questionnaires (n = 203), interviews, and group consultation with schoolchildren, teachers, teacher counsellors, principals, educational zone directors and parents. The HSLB intervention was seen as relevant and non-stigmatized, cost-effective if implemented after initial recovery steps, anecdotally effective in identifying and helping resolve trauma, accommodating the full range of children's daily stressors and sustainable. Gender, children's age, school size and the level of the tsunami impact for response were found to correlate with response differences. Along four dimensions previously identified in the literature (ability to triage, matching of intervention timing and focus, ability to accommodate a range of stressors and context compatibility), the HSLB Project is a promising intervention model (1) for children; (2) at group-level; (3) relating to natural disasters. The Nairobi Call to Action [WHO (2009) Nairobi Call to Action for Closing the Implementation Gap in Health Promotion. Geneva: World Health Organization] emphasized the importance of mainstreaming health promotion into priority programme areas, specifically including mental health. The HSLB Project represents the integration of health promotion practice into disaster preparedness mental health infrastructure.


ABC/XYZ estimates intracerebral hemorrhage volume as a percent of total brain volume in children.
Intracerebral hemorrhage volume (ICHV) as a percentage of total brain volume (TBV) is a strong predictor of outcome in childhood intracerebral hemorrhage with ICHV/TBV >2% associated with functional impairment. We aimed to determine whether easily performed approximations of intracerebral hemorrhage and brain volume can accurately and reliably stratify intracerebral hemorrhage by size. CT scans of 18 children with spontaneous intracerebral hemorrhage were independently reviewed by 4 neurologists. ICHV as a proportion of TBV was estimated as ABC/XYZ expressed as a percentage: A= largest axial hemorrhage diameter; B=largest axial diameter perpendicular to A on the same slice; and C=hemorrhage vertical diameter. Similarly, X=largest midline axial diameter of supratentorial brain; Y=largest axial diameter perpendicular to X; and Z=brain vertical diameter. Interrater reliability was measured with intraclass correlation coefficients. ICHV and TBV were measured using computer-assisted manual segmentation tracings to establish criterion validity. Each intracerebral hemorrhage was classified as small (< or = 2% TBV) or large (>2% TBV). Estimates of ICHV, TBV, and ICHV/TBV using the ABC/XYZ method had outstanding interrater reliability (intraclass correlation coefficient, 0.95 to 0.99). These estimates were highly correlated with volumetric measures (R2=0.77 to 0.96). Sensitivity of the ABC/XYZ method for identifying an ICHV >2% TBV was 100% (95% CI, 89% to 100%). Specificity was 95% (95% CI, 83% to 99%). The ABC/XYZ method accurately and reliably estimates ICHV and TBV in children. These values can be used to approximate quickly and easily ICHV as a percentage of TBV, which has important prognostic implications.


An Update on Physical Activity Research among Children in Hong Kong: A Scoping Review.
Similar to their Western counterparts, children in Hong Kong generally fail to reach the recommended levels of physical activity (PA). As an ultra-dense metropolis, Hong Kong is different from most Western cities. It is therefore important to update and appraise previous PA research in order to inform future PA promotion for Hong Kong children. Using a scoping review, the current study aimed to evaluate PA research among preschool and school-aged children in Hong Kong aged 3-12 years old who are at a critical development stage. Literature was searched from four English databases: Medline via EBSCOhost, SPORTDiscus, ERIC and PsycINFO via ProQuest; and three Chinese databases: CNKI, CQVIP and WAN-FANG. PA research among Hong Kong children published from 1 January 1997 to the searching date, 31 March 2020 was included. A total of 63 studies were identified, with the majority of studies focused on school-aged children as compared to preschoolers, adopted a cross-sectional design, using self-reported PA measures, and with small to medium sample sizes. We classified eligible studies into five main categories: (a) Health benefits of PA (k = 12). Consistent evidence on the health benefits of skeletal and cardiovascular capacity, quality of life, cognitive function, and sleep quality was revealed. However, inconsistent evidence was found on the benefits of weight-related indicators and academic performance. (b) Patterns of PA (k = 12). There is a general pattern of low levels of PA among Hong Kong children, in particular girls and children with special educational needs. (c) Measures of PA and related constructs (k = 11). The Chinese versions of self-reported measures of PA, PA-related social environment, and PA-related psychological constructs showed acceptable reliabilities and validities. (d) Correlates of PA (k = 18). The correlates of PA include physical environment, social environment, physical factors, psychological factors, and multiple correlates, which is in line with the social-ecological model. (e) Interventions for promoting PA (k = 10). PA interventions among Hong Kong children were conducted for healthy children, children with special educational needs, and children with cancer. Overall, there is a growing volume of PA research among children in Hong Kong in the recent decade. Yet, there is a lack of high-quality research for measuring, understanding, and promoting PA among Hong Kong children. It is highly recommended that future PA research among children should pay more attention on the preschoolers, adopting robust research design (e.g., randomized controlled trials), recruiting large and representative sample, and collecting device-assessed data.


The glnA gene of the cyanobacterium Agmenellum quadruplicatum PR-6 is nonessential for ammonium assimilation.
The glnA gene of the cyanobacterium Agmenellum quadruplicatum PR-6 (Synechococcus sp. strain PCC 7002) was isolated by complementing an Escherichia coli strain auxotrophic for glutamine (YMC11) with a PR-6 cosmid library. PR-6 glnA is a single-copy gene that encodes a deduced amino acid sequence that is highly homologous to the deduced glnA amino acid sequences reported for other bacteria. No homology was found between the PR-6 glnA flanking sequences and the ntrB, ntrC, or glnB genes of other bacteria. Northern (RNA) and primer extension analyses of PR-6 RNA revealed one predominant and several minor glnA transcripts of about 1.5 to 1.7 kb. The steady-state amounts of these transcripts increased three- to fivefold when the cells were starved for nitrogen. However, we found that mutant PR-6 cells lacking glnA were still able to use nitrate or ammonium as a sole nitrogen source. Although no RNA homologous to an internal fragment of the glnA gene could be detected in the mutant cells, they retained about 60% of wild-type glutamine biosynthetic activity. The mutant cells were more sensitive than the wild-type cells to methionine sulfoximine, a transition state analog of glutamate, a result that might indicate the presence of an additional glutamine synthetase; however, cell extracts of wild-type PR-6 cells and those lacking glnA were both able to use carbamyl phosphate instead of ammonium as a nitrogen donor for the synthesis of glutamine, a result that indicates the use of carbamyl phosphate synthetase to assimilate ammonium and produce glutamine.


"WALK30X5": a feasibility study of a physiotherapy walking programme for people with mild to moderate musculoskeletal conditions.
To explore the feasibility of delivering and evaluating a web-based walking intervention for people with long term musculoskeletal conditions (LTMCs), to determine its acceptability and the feasibility of conducting a definitive trial. Prospective randomised feasibility study, with blind outcome assessment at baseline, 3 and 6 months. Hospital based physiotherapy service. Forty one adults referred for assessment and advice for any mild/moderate LTMCs. doing <120minutes of moderate intensity activity per week. Participants randomised to: 1. Usual care: one usual physiotherapy advice and assessment session, including setting a physical activity goal and one follow up session (8 weeks). 2. "Walk30×5": session one, usual care plus intervention of walking programme. Participants were shown the website and podcasts and practiced how to use them. One follow up session (8 weeks). Primary: timed six minute walk test (T6MWT). Secondary: step count, self-reported pain, fatigue, mood, self-efficacy, happiness, objective blood pressure, peak expiratory flow rate, and self-report and accelerometer measured physical activity. Recruitment target achieved. No adverse events occurred. Adherence was high and the intervention acceptable. Loss to follow up n=3 (7%) at 3 months, n=8 (20%) at 6 months. T6MWT and step count proved suitable outcomes, unlike accelerometry. Estimated sample size for a definitive trial is 216. "Walk30×5" is ready for evaluation in a future, appropriately powered (n=216), phase III trial. If effective, the intervention will provide a cheap, highly accessible intervention to enable people with mild/moderate LTMCs to achieve UK physical activity guidelines. ISRCTN78581097.


A new software for dimensional measurements in 3D endodontic root canal instrumentation.
The main issue to be faced to get size estimates of 3D modification of the dental canal after endodontic treatment is the co-registration of the image stacks obtained through micro computed tomography (micro-CT) scans before and after treatment. Here quantitative analysis of micro-CT images have been performed by means of new dedicated software targeted to the analysis of root canal after endodontic instrumentation. This software analytically calculates the best superposition between the pre and post structures using the inertia tensor of the tooth. This strategy avoid minimization procedures, which can be user dependent, and time consuming. Once the co-registration have been achieved dimensional measurements have then been performed by contemporary evaluation of quantitative parameters over the two superimposed stacks of micro-CT images. The software automatically calculated the changes of volume, surface and symmetry axes in 3D occurring after the instrumentation. The calculation is based on direct comparison of the canal and canal branches selected by the user on the pre treatment image stack.


Metabolic syndrome and risk of incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study.
Several aspects concerning the relationship between the metabolic syndrome and incident diabetes are incompletely understood including the magnitude of the risk estimate, potential gender differences in the associations between the metabolic syndrome and incident diabetes, the associations between the components of the metabolic syndrome and incident diabetes, and whether the metabolic syndrome provides additional prediction beyond its components. To shed light on these issues, we examined the prospective association between the metabolic syndrome defined by the National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) and diabetes. We used data for 2796 men and women aged 35-65 years from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study followed for an average of 6.9 years. This analysis employed a case-cohort design that included 697 participants who developed diabetes and 2099 participants who did not. Incident diabetes was identified on the basis of self-reports and verified by contacting the patient's attending physician. The adjusted hazard ratio for the NCEP definition was 4.62 (95% confidence interval [CI]: 3.90-5.48) and that for the IDF definition was 4.59 (95% CI: 3.84-5.50). The adjusted hazard ratios for the NCEP but not IDF definition were higher for women than men. When participants who had no cardiometabolic abnormalities were used as the reference group for the NCEP definition, the adjusted hazard ratio for having 3 or more abnormalities increased to 22.50 (95% CI: 11.21-45.19). Of the five components, abdominal obesity and hyperglycemia were most strongly associated with incident diabetes. In this study population, both definitions of the metabolic syndrome provided similar estimates of relative risk for incident diabetes. The increase in risk for participants with the metabolic syndrome according to the NCEP definition was very large when contrasted with the risk among those who had no cardiometabolic abnormalities.


Alendronate inhibits VEGF expression in growth plate chondrocytes by acting on the mevalonate pathway.
Bisphosphonates decrease chondrocyte turnover at the growth plate and impact bone growth. Likewise vascular endothelial growth factor (VEGF) plays an important role in endochondral bone elongation by influencing chondrocyte turnover at the growth plate. To investigate whether the action of bisphosphonate on the growth plate works through VEGF, VEGF protein expression and isoform transcription in endochondral chondrocytes isolated from growing mice and treated with a clinically used bisphosphonate, alendronate, were assessed. Alendronate at 10microM and 100microM concentrations decreased secreted VEGF protein expression but not cell associated protein. Bisphosphonates are known to inhibit the mevalonate intracellular signaling pathway used by VEGF. Addition of the mevalonate pathway intermediates farnesol (FOH) and geranylgeraniol (GGOH) interacted with the low concentration of alendronate to further decrease secreted VEGF protein whereas FOH partially restored VEGF protein secretion when combined with the high alendronate. Similar to the protein data, the addition of alendronate decreased VEGF mRNA isoforms. VEGF mRNA levels were rescued by the GGOH mevalonate pathway intermediate at the low alendronate dose whereas neither intermediate consistently restored the VEGF mRNA levels at the high alendronate dose. Thus, the bisphophonate alendronate impairs growth plate chondrocyte turnover by down-regulating the secreted forms of VEGF mRNA and protein by inhibiting the mevalonate pathway.


Quantitative assessment of social and economic impact of African swine fever outbreaks in northern Uganda.
African swine fever (ASF) is one of the most important pig diseases, causing high case fatality rate and trade restrictions upon reported outbreaks. In Uganda, a low-income country with the largest pig population in East Africa, ASF is endemic. Animal disease impact is multidimensional and include social and economic impact along the value chain. In low-income settings, this impact keep people poor and push those that have managed to escape poverty back again. If the diseases can be controlled, their negative consequences can be mitigated. However, to successfully argue for investment in disease control, its cost-benefits need to be demonstrated. One part in the cost-benefit equations is disease impact quantification. The objective of this study was therefore to investigate the socio-economic impact of ASF outbreaks at household level in northern Uganda. In a longitudinal study, structured interviews with two hundred, randomly selected, pig-keeping households were undertaken three times with a six month interval. Questions related to family and pig herd demographics, pig trade and pig business. Associations between ASF outbreaks and economic and social impact variables were evaluated using linear regression models. The study showed that pigs were kept in extreme low-input-low-output farming systems involving only small monetary investments. Yearly incidence of ASF on household level was 19%. Increasing herd size was positively associated with higher economic output. The interaction between ASF outbreaks and the herd size showed that ASF outbreaks were negatively associated with economic output at the second interview occasion and with one out of two economic impact variables at the third interview occasion. No significant associations between the social impact variables included in the study and ASF outbreaks could be established. Trade and consumption of sick and dead pigs were coping strategies used to minimize losses of capital and animal protein. The results indicate that causality of social and economic impact of ASF outbreaks in smallholder systems is complex. Pigs are mostly kept as passive investments rather than active working capital, complicating economic analyses and further disqualifying disease control arguments based only on standard economic models.


Uncertainty in assessment of radiation-induced diffusion index changes in individual patients.
The purpose of this study is to evaluate repeatability coefficients of diffusion tensor indices to assess whether longitudinal changes in diffusion indices were true changes beyond the uncertainty for individual patients undergoing radiation therapy (RT). Twenty-two patients who had low-grade or benign tumors and were treated by partial brain radiation therapy (PBRT) participated in an IRB-approved MRI protocol. The diffusion tensor images in the patients were acquired pre-RT, week 3 during RT, at the end of RT, and 1, 6, and 18 months after RT. As a measure of uncertainty, repeatability coefficients (RC) of diffusion indices in the segmented cingulum, corpus callosum, and fornix were estimated by using test-retest diffusion tensor datasets from the National Biomedical Imaging Archive (NBIA) database. The upper and lower limits of the 95% confidence interval of the estimated RC from the test and retest data were used to evaluate whether the longitudinal percentage changes in diffusion indices in the segmented structures in the individual patients were beyond the uncertainty and thus could be considered as true radiation-induced changes. Diffusion indices in different white matter structures showed different uncertainty ranges. The estimated RC for fractional anisotropy (FA) ranged from 5.3% to 9.6%, for mean diffusivity (MD) from 2.2% to 6.8%, for axial diffusivity (AD) from 2.4% to 5.5%, and for radial diffusivity (RD) from 2.9% to 9.7%. Overall, 23% of the patients treated by RT had FA changes, 44% had MD changes, 50% had AD changes, and 50% had RD changes beyond the uncertainty ranges. In the fornix, 85.7% and 100% of the patients showed changes beyond the uncertainty range at 6 and 18 months after RT, demonstrating that radiation has a pronounced late effect on the fornix compared to other segmented structures. It is critical to determine reliability of a change observed in an individual patient for clinical decision making. Assessments of the repeatability and confidence interval of diffusion tensor measurements in white matter structures allow us to determine the true longitudinal change in individual patients.


The annotation of RNA motifs.
The recent deluge of new RNA structures, including complete atomic-resolution views of both subunits of the ribosome, has on the one hand literally overwhelmed our individual abilities to comprehend the diversity of RNA structure, and on the other hand presented us with new opportunities for comprehensive use of RNA sequences for comparative genetic, evolutionary and phylogenetic studies. Two concepts are key to understanding RNA structure: hierarchical organization of global structure and isostericity of local interactions. Global structure changes extremely slowly, as it relies on conserved long-range tertiary interactions. Tertiary RNA-RNA and quaternary RNA-protein interactions are mediated by RNA motifs, defined as recurrent and ordered arrays of non-Watson-Crick base-pairs. A single RNA motif comprises a family of sequences, all of which can fold into the same three-dimensional structure and can mediate the same interaction(s). The chemistry and geometry of base pairing constrain the evolution of motifs in such a way that random mutations that occur within motifs are accepted or rejected insofar as they can mediate a similar ordered array of interactions. The steps involved in the analysis and annotation of RNA motifs in 3D structures are: (a) decomposition of each motif into non-Watson-Crick base-pairs; (b) geometric classification of each basepair; (c) identification of isosteric substitutions for each basepair by comparison to isostericity matrices; (d) alignment of homologous sequences using the isostericity matrices to identify corresponding positions in the crystal structure; (e) acceptance or rejection of the null hypothesis that the motif is conserved.


1,2,4-Triazolyl 5-Azaspiro[2.4]heptanes: Lead Identification and Early Lead Optimization of a New Series of Potent and Selective Dopamine D3 Receptor Antagonists.
A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.


Development and Validation of Nomograms Predictive of Axillary Nodal Status to Guide Surgical Decision-Making in Early-Stage Breast Cancer.
Purpose: To develop and validate nomogram models using noninvasive imaging parameters with related clinical variables to predict the extent of axillary nodal involvement and stratify treatment options based on the essential cut-offs for axillary surgery according to the ACOSOG Z0011 criteria. Materials and Methods: From May 2007 to December 2017, 1799 patients who underwent preoperative breast and axillary magnetic resonance imaging (MRI) were retrospectively studied. Patients with data on axillary ultrasonography (AUS) were enrolled. The MRI images were interpreted according to Breast Imaging Reporting and Data system (BI-RADS). Using logistic regression analyses, nomograms were developed to visualize the associations between the predictors and each lymph node (LN) status endpoint. Predictive performance was assessed based on the area under the receiver operating characteristic curve (AUC). Bootstrap resampling was performed for internal validation. Goodness-of-fit of the models was evaluated using the Hosmer-Lemeshow test. Results: Of 397 early breast cancer patients, 200 (50.4%) had disease-free axilla, 119 (30.0%) had 1 or 2 positive LNs, and 78 (19.6%) had ≥3 positive LNs. Patient age, MRI features (mass margin, LN margin, presence/absence of LN hilum, and LN symmetry/asymmetry), and AUS descriptors (presence of cortical thickening or hilum) were identified as predictors of nodal disease. Nomograms with these predictors showed good calibration and discrimination; the AUC was 0.809 for negative axillary node (N0) vs. any LN metastasis, 0.749 for 1 or 2 involved nodes vs. N0, and 0.874 for ≥3 nodes vs. ≤2 metastatic nodes. The predictive ability of the 3 nomograms with additional pathological variables was significantly greater. Conclusion: The nomograms could predict the extent of ALN metastasis and facilitate decision-making preoperatively.


Matching visual saliency to confidence in plots of uncertain data.
Conveying data uncertainty in visualizations is crucial for preventing viewers from drawing conclusions based on untrustworthy data points. This paper proposes a methodology for efficiently generating density plots of uncertain multivariate data sets that draws viewers to preattentively identify values of high certainty while not calling attention to uncertain values. We demonstrate how to augment scatter plots and parallel coordinates plots to incorporate statistically modeled uncertainty and show how to integrate them with existing multivariate analysis techniques, including outlier detection and interactive brushing. Computing high quality density plots can be expensive for large data sets, so we also describe a probabilistic plotting technique that summarizes the data without requiring explicit density plot computation. These techniques have been useful for identifying brain tumors in multivariate magnetic resonance spectroscopy data and we describe how to extend them to visualize ensemble data sets.