A hybrid-stress finite element for linear anisotropic elasticity

Standard assumed displacement finite elements with anisotropic material properties perform poorly in complex stress fields such as combined bending and shear and combined bending and torsion. A set of three dimensional hybrid-stress brick elements were developed with fully anisotropic material properties. Both eight-node and twenty-node bricks were developed based on the symmetry group theory of Punch and Atluri. An eight-node brick was also developed using complete polynomials and stress basis functions and reducing the order of the resulting stress parameter matrix by applying equilibrium constraints and stress compatibility constraints. Here the stress compatibility constraints must be formulated assuming anisotropic material properties. The performance of these elements was examined in numerical examples covering a broad range of stress distributions. The stress predictions show significant improvement over the assumed displacement elements but the calculation time is increased

SplicerAV: a tool for mining microarray expression data for changes in RNA processing

<p>Abstract</p> <p>Background</p> <p>Over the past two decades more than fifty thousand unique clinical and biological samples have been assayed using the Affymetrix HG-U133 and HG-U95 GeneChip microarray platforms. This substantial repository has been used extensively to characterize changes in gene expression between biological samples, but has not been previously mined <it>en masse </it>for changes in mRNA processing. We explored the possibility of using HG-U133 microarray data to identify changes in alternative mRNA processing in several available archival datasets.</p> <p>Results</p> <p>Data from these and other gene expression microarrays can now be mined for changes in transcript isoform abundance using a program described here, SplicerAV. Using <it>in vivo </it>and <it>in vitro </it>breast cancer microarray datasets, SplicerAV was able to perform both gene and isoform specific expression profiling within the same microarray dataset. Our reanalysis of Affymetrix U133 plus 2.0 data generated by <it>in vitro </it>over-expression of HRAS, E2F3, beta-catenin (CTNNB1), SRC, and MYC identified several hundred oncogene-induced mRNA isoform changes, one of which recognized a previously unknown mechanism of <it>EGFR </it>family activation. Using clinical data, SplicerAV predicted 241 isoform changes between low and high grade breast tumors; with changes enriched among genes coding for guanyl-nucleotide exchange factors, metalloprotease inhibitors, and mRNA processing factors. Isoform changes in 15 genes were associated with aggressive cancer across the three breast cancer datasets.</p> <p>Conclusions</p> <p>Using SplicerAV, we identified several hundred previously uncharacterized isoform changes induced by <it>in vitro </it>oncogene over-expression and revealed a previously unknown mechanism of EGFR activation in human mammary epithelial cells. We analyzed Affymetrix GeneChip data from over 400 human breast tumors in three independent studies, making this the largest clinical dataset analyzed for <it>en masse </it>changes in alternative mRNA processing. The capacity to detect RNA isoform changes in archival microarray data using SplicerAV allowed us to carry out the first analysis of isoform specific mRNA changes directly associated with cancer survival.</p

Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration

Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson's disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer's disease and Huntington's disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders

Implementation of geriatric assessment in oncology settings: A systematic realist review

Older adults with cancer are more likely to have worse clinical outcomes than their younger counterparts, and shared decision-making can be difficult, due to both complexity from adverse ageing and under-representation in clinical trials. Geriatric assessment (GA) has been increasingly recognised as a predictive and prehabilitative tool for older adults with cancer. However, GA has been notoriously difficult to implement in oncological settings due to workforce, economic, logistical, and practical barriers. We aimed to review the heterogenous literature on implementation of GA in oncology settings to understand the different implementation context configurations of GA and the mechanisms they trigger to enable successful implementation. A systematic realist review was undertaken in two stages: i) systematic searches with structured data extraction combined with iterative key stakeholder consultations to develop programme theories for implementing GA in oncology settings; ii) synthesis to refine programme theories. Medline, Embase, PsycInfo, Cochrane Library, CINAHL, Web of Science, Scopus, ASSIA, Epistemonikos, JBI Database of Systematic Reviews and Implementation Reports, DARE and Health Technology Assessment were searched. Four programme theories were developed from 53 included articles and 20 key stakeholder consultations addressing the major barriers of GA implementation in oncology practice: time (leveraging non-specialists), funding (creating favourable health economics), practicalities (establishing the use of GA in cancer care), and managing limited resources. We demonstrate that a whole system approach is required to improve the implementation of GA in cancer settings. This review will help inform policy decisions regarding implementation of GA and provide a basis for further implementation research

From programme theory to logic models for multispecialty community providers: a realist evidence synthesis

BackgroundThe NHS policy of constructing multispecialty community providers (MCPs) rests on a complex set of assumptions about how health systems can replace hospital use with enhanced primary care for people with complex, chronic or multiple health problems, while contributing savings to health-care budgets.ObjectivesTo use policy-makers’ assumptions to elicit an initial programme theory (IPT) of how MCPs can achieve their outcomes and to compare this with published secondary evidence and revise the programme theory accordingly.DesignRealist synthesis with a three-stage method: (1) for policy documents, elicit the IPT underlying the MCP policy, (2) review and synthesise secondary evidence relevant to those assumptions and (3) compare the programme theory with the secondary evidence and, when necessary, reformulate the programme theory in a more evidence-based way.Data sourcesSystematic searches and data extraction using (1) the Health Management Information Consortium (HMIC) database for policy statements and (2) topically appropriate databases, including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Applied Social Sciences Index and Abstracts (ASSIA). A total of 1319 titles and abstracts were reviewed in two rounds and 116 were selected for full-text data extraction. We extracted data using a formal data extraction tool and synthesised them using a framework reflecting the main policy assumptions.ResultsThe IPT of MCPs contained 28 interconnected context–mechanism–outcome relationships. Few policy statements specified what contexts the policy mechanisms required. We found strong evidence supporting the IPT assumptions concerning organisational culture, interorganisational network management, multidisciplinary teams (MDTs), the uses and effects of health information technology (HIT) in MCP-like settings, planned referral networks, care planning for individual patients and the diversion of patients from inpatient to primary care. The evidence was weaker, or mixed (supporting some of the constituent assumptions but not others), concerning voluntary sector involvement, the effects of preventative care on hospital admissions and patient experience, planned referral networks and demand management systems. The evidence about the effects of referral reductions on costs was equivocal. We found no studies confirming that the development of preventative care would reduce demands on inpatient services. The IPT had overlooked certain mechanisms relevant to MCPs, mostly concerning MDTs and the uses of HITs.LimitationsThe studies reviewed were limited to Organisation for Economic Co-operation and Development countries and, because of the large amount of published material, the period 2014–16, assuming that later studies, especially systematic reviews, already include important earlier findings. No empirical studies of MCPs yet existed.ConclusionsMultidisciplinary teams are a central mechanism by which MCPs (and equivalent networks and organisations) work, provided that the teams include the relevant professions (hence, organisations) and, for care planning, individual patients. Further primary research would be required to test elements of the revised logic model, in particular about (1) how MDTs and enhanced general practice compare and interact, or can be combined, in managing referral networks and (2) under what circumstances diverting patients from in-patient to primary care reduces NHS costs and improves the quality of patient experience.Study registrationThis study is registered as PROSPERO CRD42016038900.FundingThe National Institute for Health Research (NIHR) Health Services and Delivery Research programme and supported by the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula

Jedi public health: Co-creating an identity-safe culture to promote health equity

© 2016 The Authors. The extent to which socially-assigned and culturally mediated social identity affects health depends on contingencies of social identity that vary across and within populations in day-to-day life. These contingencies are structurally rooted and health damaging inasmuch as they activate physiological stress responses. They also have adverse effects on cognition and emotion, undermining self-confidence and diminishing academic performance. This impact reduces opportunities for social mobility, while ensuring those who "beat the odds" pay a physical price for their positive efforts. Recent applications of social identity theory toward closing racial, ethnic, and gender academic achievement gaps through changing features of educational settings, rather than individual students, have proved fruitful. We sought to integrate this evidence with growing social epidemiological evidence that structurally-rooted biopsychosocial processes have population health effects. We explicate an emergent framework, Jedi Public Health (JPH). JPH focuses on changing features of settings in everyday life, rather than individuals, to promote population health equity, a high priority, yet, elusive national public health objective. We call for an expansion and, in some ways, a re-orienting of efforts to eliminate population health inequity. Policies and interventions to remove and replace discrediting cues in everyday settings hold promise for disrupting the repeated physiological stress process activation that fuels population health inequities with potentially wide application.National Institute on Aging (Grant # R01 AG032632)National Institute on Aging (Grant # T32 AG00221

Basal body stability and ciliogenesis requires the conserved component Poc1

Centrioles are the foundation for centrosome and cilia formation. The biogenesis of centrioles is initiated by an assembly mechanism that first synthesizes the ninefold symmetrical cartwheel and subsequently leads to a stable cylindrical microtubule scaffold that is capable of withstanding microtubule-based forces generated by centrosomes and cilia. We report that the conserved WD40 repeat domain–containing cartwheel protein Poc1 is required for the structural maintenance of centrioles in Tetrahymena thermophila. Furthermore, human Poc1B is required for primary ciliogenesis, and in zebrafish, DrPoc1B knockdown causes ciliary defects and morphological phenotypes consistent with human ciliopathies. T. thermophila Poc1 exhibits a protein incorporation profile commonly associated with structural centriole components in which the majority of Poc1 is stably incorporated during new centriole assembly. A second dynamic population assembles throughout the cell cycle. Our experiments identify novel roles for Poc1 in centriole stability and ciliogenesis

Vaccination with Human Hookworm Vaccine Necator americanus Aspartic Protease-1 M74 Generates Neutralizing Antibodies and a Potent Immune Response in BALB/c Mice

Backgound: Human Hookworm Infection, a neglected tropical disease infects more than 600 million people around the world. Hookworms ingest hemoglobin containing erythrocytes and Necator americanus Aspartic Protease-1 wild type (Na-APR-1wt) a hemoglobinase cleaves hemoglobin to form Heme and Globin. Globin is further digested by other gut enzymes and the nutritional end products are absorbed by the hookworm’s gut wall. Also, Heme which is toxic to hookworm is detoxified by the Necator americanus Glutathione Transferase-1 (Na-GST-1) a detoxification enzyme secreted by the gut of the hookworm. Necator americanus Aspartic Protease-1 M74 (Na-APR-1 M74) is the new vaccine for the Human Hookworm Infection which is currently under pre-clinical development. Na-APR-1 M74 vaccine is an Alhydrogel® adjuvanted vaccine containing the mutant form of the Na-APR-1wt. Neutralizing Na-APR-1wt by potent antibodies (IgG) in the vaccinees will block the initiation of the hemoglobin digestion cascade and starve the hookworms from essential nutrition, leading to their death. Here, we report the results of the neutralizing capacity of antibodies and potency (immunogenicity) of Na-APR-1 M74 vaccine in BALB/c mice. Methods: Serum for IgG was generated by vaccinating BALB/c mice twice subcutaneously with Na-APR-1 M74 an enzymatically inactive mutant form of Na-APR-1wt formulated with Alhydrogel®. Assessment of neutralizing capacity of IgG was performed using the standard Cathepsin-D protease assay using MOCAc substrate. Dose response (% Inhibition vs Dose) was assessed using linear regression analysis. Potency testing of the Na-APR-1M74 clinical drug product was performed by standard bioassay. Median Effective Dose 50 (ED50) with the 95% fiducial limits (95%FL) was estimated using Probit Analysis (SAS® 9.3). Also, Relative Potency (RP) was estimated by the methods described in European Pharmacopeia\u27s Chapter 5.3. Results: Five microgram of IgG neutralized 51.06% of the enzymatic activity of 250ng of Na-APR-1wt. An excellent dose response was also observed. ED50 of 14.15μg (95%FL = 10.47μg -- 18.93μg) and 11.46μg (95%FL = 4.86μg --27.42μg) was estimated for time 1 and 7 month post manufacture respectively. RP at 7 months was found to be 1.23 (95%FL = 0.792--1.917). Conclusion: These preclinical results of the Na-APR-1 M74 vaccine lay the foundation for a Phase 1 Clinical Trial in USA and Brazil. This Na-APR-1 M74 vaccine will be subsequently combined with Necator americanus Glutathione transferase-1 (Na-GST-1) vaccine to form a multivalent human hookworm vaccine

Impact of medications prescribed for treatment of attention-deficit hyperactivity disorder on physical growth in children and adolescents with HIV.

OBJECTIVE: To examine the relationships between physical growth and medications prescribed for symptoms of attention-deficit hyperactivity disorder in children with HIV. METHODS: Analysis of data from children with perinatally acquired HIV (N = 2251; age 3-19 years), with and without prescriptions for stimulant and nonstimulant medications used to treat attention-deficit hyperactivity disorder, in a long-term observational study. Height and weight measurements were transformed to z scores and compared across medication groups. Changes in z scores during a 2-year interval were compared using multiple linear regression models adjusting for selected covariates. RESULTS: Participants with (n = 215) and without (n = 2036) prescriptions were shorter than expected based on US age and gender norms (p \u3c .001). Children without prescriptions weighed less at baseline than children in the general population (p \u3c .001) but gained height and weight at a faster rate (p \u3c .001). Children prescribed stimulants were similar to population norms in baseline weight; their height and weight growth velocities were comparable with the general population and children without prescriptions (for weight, p = .511 and .100, respectively). Children prescribed nonstimulants had the lowest baseline height but were similar to population norms in baseline weight. Their height and weight growth velocities were comparable with the general population but significantly slower than children without prescriptions (p = .01 and .02, respectively). CONCLUSION: The use of stimulants to treat symptoms of attention-deficit hyperactivity disorder does not significantly exacerbate the potential for growth delay in children with HIV and may afford opportunities for interventions that promote physical growth. Prospective studies are needed to confirm these findings

Implementing the battery-operated hand-held fan as an evidence-based, non-pharmacological intervention for chronic breathlessness in patients with chronic obstructive pulmonary disease (COPD): a qualitative study of the views of specialist respiratory clinicians

INTRODUCTION: The battery-operated hand-held fan ('fan') is an inexpensive and portable non-pharmacological intervention for chronic breathlessness. Evidence from randomised controlled trials suggests the fan reduces breathlessness intensity and improves physical activity in patients with a range of advanced chronic conditions. Qualitative data from these trials suggests the fan may also reduce anxiety and improve daily functioning for many patients. This study aimed to explore barriers and facilitators to the fan's implementation in specialist respiratory care as a non-pharmacological intervention for chronic breathlessness in patients with chronic obstructive pulmonary disease (COPD). METHODS: A qualitative approach was taken, using focus groups. Participants were clinicians from any discipline working in specialist respiratory care at two hospitals. Questions asked about current fan-related practice and perceptions regarding benefits, harms and mechanisms, and factors influencing its implementation. Analysis used a mixed inductive/deductive approach. RESULTS: Forty-nine participants from nursing (n = 30), medical (n = 13) and allied health (n = 6) disciplines participated across 9 focus groups. The most influential facilitator was a belief that the fan's benefits outweighed disadvantages. Clinicians' beliefs about the fan's mechanisms determined which patient sub-groups they targeted, for example anxious or palliative/end-stage patients. Barriers to implementation included a lack of clarity about whose role it was to implement the fan, what advice to provide patients, and limited access to fans in hospitals. Few clinicians implemented the fan for acute-on-chronic breathlessness or in combination with other interventions. CONCLUSION: Implementation of the fan in specialist respiratory care may require service- and clinician-level interventions to ensure it is routinely recommended as a first-line intervention for chronic breathlessness in patients for whom this symptom is of concern, regardless of COPD stage