Effectiveness and reach of a directed-population approach to improving dental health and reducing inequalities: a cross sectional study

Background Childsmile School adopts a directed-population approach to target fluoride varnish applications to 20% of the primary one (P1) population in priority schools selected on the basis of the proportion of enrolled children considered to be at increased-risk of developing dental caries. The study sought to compare the effectiveness of four different methods for identifying individuals most in need when a directed-population approach is taken. <p></p> Methods The 2008 Basic National Dental Inspection Programme (BNDIP) cross-sectional P1 Scottish epidemiological survey dataset was used to model four methods and test three definitions of increased-risk. Effectiveness was determined by the positive predictive value (PPV) and explored in relation to 1-sensitivity and 1-specificity. <p></p> Results Complete data was available on 43470 children (87% of the survey). At the Scotland level, at least half (50%) of the children targeted were at increased-risk irrespective of the method used to target or the definition of increased-risk. There was no one method across all definitions of <i>increased-risk</i> that maximised PPV. Instead, PPV was highest when the targeting method complimented the definition of <i>increased-risk</i>. There was a higher percentage of children at <i>increased-risk</i> who were not targeted (1-sensitivity) when caries experience (rather than deprivation) was used to define <i>increased-risk</i>, irrespective of the method used for targeting. Over all three definitions of <i>increased-risk</i>, there was no one method that minimised (1-sensitivity) although this was lowest when the method and definition of <i>increased-risk</i> were complimentary. The false positive rate (1-specificity) for all methods and all definitions of <i>increased-risk</i> was consistently low (<20%), again being lowest when the method and definition of <i>increased-risk</i> were complimentary. <p></p> Conclusion Developing a method to reach all (or even the vast majority) of individuals at <i>increased-risk</i> defined by either caries experience or deprivation is difficult using a directed-population approach at a group level. There is a need for a wider debate between politicians and public health experts to decide how best to reach those most at need of intervention to improve health and reduce inequalities. <p></p&gt

Development of hepatic pathology in GBV‐B‐infected red‐bellied tamarins (Saguinus labiatus)

GB virus B (GBV‐B) is a new world monkey‐associated flavivirus used to model acute hepatitis C virus (HCV) infection. Critical for evaluation of antiviral or vaccine approaches is an understanding of the effect of HCV on the liver at different stages of infection. In the absence of longitudinal human tissue samples at defined time points, we have characterized changes in tamarins. As early as 2 weeks post‐infection histological changes were noticeable, and these were established in all animals by 6 weeks. Despite high levels of liver‐associated viral RNA, there was reversal of hepatic damage on clearance of peripheral virus though fibrosis was demonstrated in four tamarins. Notably, viral RNA burden in the liver dropped to near undetectable or background levels in all animals which underwent a second viral challenge, highlighting the efficacy of the immune response in removing foci of replication in the liver. These data add to the knowledge of GBV‐B infection in New World primates which can offer attractive systems for the testing of prophylactic and therapeutic treatments and the evaluation of their utility in preventing or reversing liver pathology

Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney

BACKGROUND: The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective). RESULTS: In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE(2), 6-keto-PGF1(α,) TxB(2)), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml(−1) h(−1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE(2) excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB(2) excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD). CONCLUSIONS: These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0598-z) contains supplementary material, which is available to authorized users

Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP

Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK modul

Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies

Exchanging knowledge to improve organic arable farming: an evaluation of knowledge exchange tools with farmer groups across Europe

Organic farming is knowledge intensive. To support farmers in improving yields and organic agriculture systems, there is a need to improve how knowledge is shared. There is an established culture of sharing ideas, successes and failures in farming. The internet and information technologies open up new opportunities for knowledge exchange involving farmers, researchers, advisors and other practitioners. The OK-Net Arable brought together practitioners from regional Farmer Innovation Groups across Europe in a multi-actor project to explore how online knowledge exchange could be improved. Feedback from the groups was obtained for 35 ‘tools’, defined as end-user materials, such as technical guides, videos and websites informing about practices in organic agriculture. The groups also selected one practice to test on farms, sharing their experiences with others through workshops, exchange visits and through videos

CD98hc facilitates B cell proliferation and adaptive humoral immunity.

The proliferation of antigen-specific lymphocytes and resulting clonal expansion are essential for adaptive immunity. We report here that B cell-specific deletion of the heavy chain of CD98 (CD98hc) resulted in lower antibody responses due to total suppression of B cell proliferation and subsequent plasma cell formation. Deletion of CD98hc did not impair early B cell activation but did inhibit later activation of the mitogen-activated protein kinase Erk1/2 and downregulation of the cell cycle inhibitor p27. Reconstitution of CD98hc-deficient B cells with CD98hc mutants showed that the integrin-binding domain of CD98hc was required for B cell proliferation but that the amino acid-transport function of CD98hc was dispensable for this. Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored the appearance of CD98hc in vertebrates

Analysis of Laser Ultrasonic Measurements of Surface Waves on Elastic Spheres

In conventional ultrasonic nondestructive evaluation studies, piezoelectric transducers are used to generate sound waves in solids via a couplant that transmits the mechanical motions. In recent years, a different method of generating sound in solids, pulsed laser heating, was introduced by White [1,2]. This method is noncontacting, requires no coupling medium, and operates directly on the surface of the specimen. Noncontacting ultrasonic detection using laser interferometers of several types has also been developed [3]. Laser techniques can achieve essentially point source and point detection of ultrasonic motion through focusing. Laser ultrasonics can, therefore, be used on objects with complex shapes, e.g. curved surfaces, and are applicable to material shapes more commonly found in industry. Often the goal of ultrasonic measurements is to determine material properties such as Lame’s elastic constants. The conventional approach measures longitudinal and shear wave speeds between two parallel flat surfaces. The work reported here demonstrates the versatility of laser ultrasonics by directly measuring the surface motion of a solid sphere generated by ablation from a pulsed laser beam. The results compare well with elastodynamic theoretical calculations, where the ablation source is approximated as a normal impulse on the surface. This work suggests that an algorithm could be formulated to measure elastic properties of targets with curved surfaces

North Flinders Reef (Coral Sea, Australia) Porites sp. corals as a candidate Global Boundary Stratotype Section and Point for the Anthropocene Series

Corals are unique in the suite of proposed Anthropocene Global Boundary Stratotype Section and Point (GSSP) archives, as living organisms that produce aragonite exoskeletons preserved in the geological record that contain highly accurate and precise (<±1 year) internal chronologies. The GSSP candidate site North Flinders Reef in the Coral Sea (Australia) is an offshore oceanic reef, and therefore less vulnerable to local human influences than those closer to the coast. Here, we present geochemical records from two Porites sp. corals sampled at an annual to pluri-annual (i.e. 3–5 years) resolution that shows clear global and regional human impacts. Atmospheric nuclear bomb testing by-products (14C,239+240Pu) show a clear increase in the Flinders Reef corals coincident with well-dated nuclear testing operations. By contrast, the radionuclides 241Am and 137Cs are present at low or undetectable levels, as are spheroidal carbonaceous fly-ash particles. Coral δ13C shows centennial variability likely influenced by growth effects in the 18th century and with a progression to lower values starting in 1880 and accelerating post-1970. The latter may be related to the Suess Effect resulting from 13C-depleted fossil fuel burning. Coral δ15N decreased between 1710 and 1954 with a reversal post-1954. Coral temperature proxies indicate prominent centennial variability with equally warm conditions in the 18th and end of 20th century. However, the exact mechanisms responsible for the mid-20th century changes in these parameters need to be scrutinised in further detail. Plain Language summary: This work proposes a candidate natural archive for the official marker of the Anthropocene that geologists will use to mark this important interval in time. Our candidate is a live coral from North Flinders Reef in the Coral Sea (Australia), located 150 km east of the Great Barrier Reef, a location that is remote from direct local human influences. Corals are a unique archive of tropical ocean change because they incorporate the geochemical signature from seawater into their limestone skeleton during their long life-spans. Here we investigated a number of geochemical markers in yearly growth layers of the corals to define several markers for the Anthropocene based on changes in temperature, water chemistry, chemicals from pollution and fertilisers, radioactive products from nuclear bomb testing, and by-products from burning fossil fuels. We have detected clear human influences in several of these markers

The evolutionary dynamics of extrachromosomal DNA in human cancers

Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer