Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres

Regulated expression of matrix metalloproteinases, inflammatory mediators, and endometrial matrix remodeling by 17beta-estradiol in the immature rat uterus

<p>Abstract</p> <p>Background</p> <p>Administration of a single physiological dose of 17beta-estradiol (E2:40 microg/kg) to the ovariectomized immature rat rapidly induces uterine growth and remodeling. The response is characterized by changes in endometrial stromal architecture during an inflammatory-like response that likely involves activated matrix-metalloproteinases (MMPs). While estrogen is known as an inducer of endometrial growth, its role in specific expression of MMP family members in vivo is poorly characterized. E2-induced changes in MMP-2, -3, -7, and -9 mRNA and protein expression were analyzed to survey regulation along an extended time course 0-72 hours post-treatment. Because E2 effects inflammatory-like changes that may alter MMP expression, we assessed changes in tissue levels of TNF-alpha and MCP-1, and we utilized dexamethasone (600 microg/kg) to better understand the role of inflammation on matrix remodeling.</p> <p>Methods</p> <p>Ovariectomized 21 day-old female Sprague-Dawley rats were administered E2 and uterine tissues were extracted and prepared for transmission electron microscopy (TEM), mRNA extraction and real-time RT-PCR, protein extraction and Western blot, or gelatin zymography. In inhibitor studies, pretreatment compounds were administered prior to E2 and tissues were harvested at 4 hours post-hormone challenge.</p> <p>Results</p> <p>Using a novel TEM method to quantitatively assess changes in stromal collagen density, we show that E2-induced matrix remodeling is rapid in onset (< 1 hour) and leads to a 70% reduction in collagen density by 4 hours. Matrix remodeling is MMP-dependent, as pretreatment with batimastat ablates the hormone effect. MMP-3, -7, and -9 and inflammatory markers (TNF-alpha and MCP-1) are transiently upregulated with peak expression at 4 hours post-E2 treatment. MMP-2 expression is increased by E2 but highest expression and activity occur later in the response (48 hours). Dexamethasone inhibits E2-modulated changes in collagen density and expression of MMPs although these effects are variable. Dexamethasone upregulates MMP-3 mRNA but not protein levels, inhibiting E2-induced upregulation of MMP-7, and -9, and MCP-1 mRNA and protein but not inhibiting the hormone-induced increase in TNF-alpha mRNA.</p> <p>Conclusion</p> <p>The data demonstrate that E2-regulated endometrial remodeling is rapid in onset (<1 hour) and peak expression of MMPs and inflammatory mediators correlates temporally with the period of lowest stromal collagen density during uterine tissue hypertrophy.</p

Limited Relationship between Cervico-Vaginal Fluid Cytokine Profiles and Cervical Shortening in Women at High Risk of Spontaneous Preterm Birth

Objective: to determine the relationship between high vaginal pro-inflammatory cytokines and cervical shortening in women at high risk of spontaneous preterm labor and to assess the influence of cervical cerclage and vaginal progesterone on this relationship. Methods: this prospective longitudinal observational study assessed 112 women with at least one previous preterm delivery between 16 and 34 weeks’ gestation. Transvaginal cervical length was measured and cervico-vaginal fluid sampled every two weeks until 28 weeks. If the cervix shortened (<25 mm) before 24 weeks’ gestation, women (cases) were randomly assigned to cerclage or progesterone and sampled weekly. Cytokine concentrations were measured in a subset of cervico-vaginal fluid samples (n = 477 from 78 women) by 11-plex fluid-phase immunoassay. Results: all 11 inflammatory cytokines investigated were detected in cervico-vaginal fluid from women at high risk of preterm birth, irrespective of later cervical shortening. At less than 24 weeks’ gestation and prior to intervention, women destined to develop a short cervix (n = 36) exhibited higher cervico-vaginal concentrations than controls (n = 42) of granulocyte-macrophage colony-stimulating factor [(GM-CSF) 16.2 fold increase, confidence interval (CI) 1.8–147; p = 0.01] and monocyte chemotactic protein-1 [(MCP-1) 4.8, CI 1.0–23.0; p = 0.05]. Other cytokines were similar between cases and controls. Progesterone treatment did not suppress cytokine concentrations. Interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor (G-CSF), interferon (IFN)-γ and tumour necrosis factor (TNF)-α concentrations were higher following randomization to cerclage versus progesterone (p<0.05). Cerclage, but not progesterone treatment, was followed by a significant increase in cervical length [mean 11.4 mm, CI 5.0–17.7; p<0.001]. Conclusions: although GM-CSF and MCP-1 cervico-vaginal fluid concentrations were raised, the majority of cervico-vaginal cytokines did not increase in association with cervical shortening. Progesterone treatment showed no significant anti-inflammation action on cytokine concentrations. Cerclage insertion was associated with an increase in the majority of inflammatory markers and cervical length

A genome-wide association study identifies multiple loci for variation in human ear morphology

Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10−8 to 3 × 10−14). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC

The learning styles neuromyth:when the same term means different things to different teachers

Alexia Barrable - ORCID: 0000-0002-5352-8330 https://orcid.org/0000-0002-5352-8330Although learning styles (LS) have been recognised as a neuromyth, they remain a virtual truism within education. A point of concern is that the term LS has been used within theories that describe them using completely different notions and categorisations. This is the first empirical study to investigate education professionals’ conceptualisation, as well as means of identifying and implementing LS in their classroom. A sample of 123 education professionals were administered a questionnaire consisting both closed- and open-ended questions. Responses were analysed using thematic analysis. LS were found to be mainly conceptualised within the Visual-Auditory-(Reading)-Kinaesthetic (VAK/VARK) framework, as well as Gardner’s multiple intelligences. Moreover, a lot of education professionals confused theories of learning (e.g., behavioural or cognitive theories) with LS. In terms of identifying LS, educators reported using a variety of methods, spanning from observation and everyday contact to the use of tests. The ways LS were implemented in the classroom were numerous, comprising various teaching aids, participatory techniques and motor activities. Overall, we argue that the extended use of the term LS gives the illusion of a consensus amongst educators, when a closer examination reveals that the term LS is conceptualised, identified and implemented idiosyncratically by different individuals. This study aims to be of use to pre-service and in-service teacher educators in their effort to debunk the neuromyth of LS and replace it with evidence-based practices.https://doi.org/10.1007/s10212-020-00485-236pubpub

Sensitivity of Anopheles gambiae population dynamics to meteo-hydrological variability: a mechanistic approach

<p>Abstract</p> <p>Background</p> <p>Mechanistic models play an important role in many biological disciplines, and they can effectively contribute to evaluate the spatial-temporal evolution of mosquito populations, in the light of the increasing knowledge of the crucial driving role on vector dynamics played by meteo-climatic features as well as other physical-biological characteristics of the landscape.</p> <p>Methods</p> <p>In malaria eco-epidemiology landscape components (atmosphere, water bodies, land use) interact with the epidemiological system (interacting populations of vector, human, and parasite). In the background of the eco-epidemiological approach, a mosquito population model is here proposed to evaluate the sensitivity of <it>An. gambiae </it>s.s. population to some peculiar thermal-pluviometric scenarios. The scenarios are obtained perturbing meteorological time series data referred to four Kenyan sites (Nairobi, Nyabondo, Kibwesi, and Malindi) representing four different eco-epidemiological settings.</p> <p>Results</p> <p>Simulations highlight a strong dependence of mosquito population abundance on temperature variation with well-defined site-specific patterns. The upper extreme of thermal perturbation interval (+ 3°C) gives rise to an increase in adult population abundance at Nairobi (+111%) and Nyabondo (+61%), and a decrease at Kibwezi (-2%) and Malindi (-36%). At the lower extreme perturbation (-3°C) is observed a reduction in both immature and adult mosquito population in three sites (Nairobi -74%, Nyabondo -66%, Kibwezi -39%), and an increase in Malindi (+11%). A coherent non-linear pattern of population variation emerges. The maximum rate of variation is +30% population abundance for +1°C of temperature change, but also almost null and negative values are obtained. Mosquitoes are less sensitive to rainfall and both adults and immature populations display a positive quasi-linear response pattern to rainfall variation.</p> <p>Conclusions</p> <p>The non-linear temperature-dependent response is in agreement with the non-linear patterns of temperature-response of the basic bio-demographic processes. This non-linearity makes the hypothesized biological amplification of temperature effects valid only for a limited range of temperatures. As a consequence, no simple extrapolations can be done linking temperature rise with increase in mosquito distribution and abundance, and projections of <it>An. gambiae </it>s.s. populations should be produced only in the light of the local meteo-climatic features as well as other physical and biological characteristics of the landscape.</p