Preclinical assessment of an anti-HTLV-1 heterologous DNA/MVA vaccine protocol expressing a multiepitope HBZ protein.

BACKGROUND: Human T-lymphotropic virus 1 (HTLV-1) is associated with the development of several pathologies and chronic infection in humans. The inefficiency of the available treatments and the challenge in developing a protective vaccine highlight the need to produce effective immunotherapeutic tools. The HTLV-1 basic leucine zipper (bZIP) factor (HBZ) plays an important role in the HTLV-1 persistence, conferring a survival advantage to infected cells by reducing the HTLV-1 proteins expression, allowing infected cells to evade immune surveillance, and enhancing cell proliferation leading to increased proviral load. METHODS: We have generated a recombinant Modified Virus Vaccinia Ankara (MVA-HBZ) and a plasmid DNA (pcDNA3.1(+)-HBZ) expressing a multiepitope protein based on peptides of HBZ to study the immunogenic potential of this viral-derived protein in BALB/c mice model. Mice were immunized in a prime-boost heterologous protocol and their splenocytes (T CD4+ and T CD8+) were immunophenotyped by flow cytometry and the humoral response was evaluated by ELISA using HBZ protein produced in prokaryotic vector as antigen. RESULTS: T CD4+ and T CD8+ lymphocytes cells stimulated by HBZ-peptides (HBZ42-50 and HBZ157-176) showed polyfunctional double positive responses for TNF-α/IFN-γ, and TNF-α/IL-2. Moreover, T CD8+ cells presented a tendency in the activation of effector memory cells producing granzyme B (CD44+High/CD62L-Low), and the activation of Cytotoxic T Lymphocytes (CTLs) and cytotoxic responses in immunized mice were inferred through the production of granzyme B by effector memory T cells and the expression of CD107a by CD8+ T cells. The overall data is consistent with a directive and effector recall response, which may be able to operate actively in the elimination of HTLV-1-infected cells and, consequently, in the reduction of the proviral load. Sera from immunized mice, differently from those of control animals, showed IgG-anti-HBZ production by ELISA. CONCLUSIONS: Our results highlight the potential of the HBZ multiepitope protein expressed from plasmid DNA and a poxviral vector as candidates for therapeutic vaccine.

A unified call to action from Australian nursing and midwifery leaders: ensuring that Black lives matter.

Nurses and midwives of Australia now is the time for change! As powerfully placed, Indigenous and non-Indigenous nursing and midwifery professionals, together we can ensure an effective and robust Indigenous curriculum in our nursing and midwifery schools of education. Today, Australia finds itself in a shifting tide of social change, where the voices for better and safer health care ring out loud. Voices for justice, equity and equality reverberate across our cities, our streets, homes, and institutions of learning. It is a call for new songlines of reform. The need to embed meaningful Indigenous health curricula is stronger now than it ever was for Australian nursing and midwifery. It is essential that nursing and midwifery leadership continue to build an authentic collaborative environment for Indigenous curriculum development. Bipartisan alliance is imperative for all academic staff to be confident in their teaching and learning experiences with Indigenous health syllabus. This paper is a call out. Now is the time for Indigenous and non-Indigenous nurses and midwives to make a stand together, for justice and equity in our teaching, learning, and practice. Together we will dismantle systems, policy, and practices in health that oppress. The Black Lives Matter movement provides us with a 'now window' of accepted dialogue to build a better, culturally safe Australian nursing and midwifery workforce, ensuring that Black Lives Matter in all aspects of health care.

Science-policy in environmental and health risk assessment: if we cannot do without, can we do better?

How can empirical evidence of adverse effects from exposure to noxious agents, which is often incomplete and uncertain, be used most appropriately to protect human health? We examine several important questions on the best uses of empirical evidence in regulatory risk management decision-making raised by the US Environmental Protection Agency (EPA)'s science-policy concerning uncertainty and variability in human health risk assessment. In our view, the US EPA (and other agencies that have adopted similar views of risk management) can often improve decision-making by decreasing reliance on default values and assumptions, particularly when causation is uncertain. This can be achieved by more fully exploiting decision-theoretic methods and criteria that explicitly account for uncertain, possibly conflicting scientific beliefs and that can be fully studied by advocates and adversaries of a policy choice, in administrative decision-making involving risk assessment. The substitution of decision-theoretic frameworks for default assumption-driven policies also allows stakeholder attitudes toward risk to be incorporated into policy debates, so that the public and risk managers can more explicitly identify the roles of risk-aversion or other attitudes toward risk and uncertainty in policy recommendations. Decision theory provides a sound scientific way explicitly to account for new knowledge and its effects on eventual policy choices. Although these improvements can complicate regulatory analyses, simplifying default assumptions can create substantial costs to society and can prematurely cut off consideration of new scientific insights (e.g., possible beneficial health effects from exposure to sufficiently low 'hormetic' doses of some agents). In many cases, the administrative burden of applying decision-analytic methods is likely to be more than offset by improved effectiveness of regulations in achieving desired goals. Because many foreign jurisdictions adopt US EPA reasoning and methods of risk analysis, it may be especially valuable to incorporate decision-theoretic principles that transcend local differences among jurisdictions.

Causation in risk assessment and management: models, inference, biases, and a microbial risk-benefit case study.

Causal inference of exposure-response relations from data is a challenging aspect of risk assessment with important implications for public and private risk management. Such inference, which is fundamentally empirical and based on exposure (or dose)-response models, seldom arises from a single set of data; rather, it requires integrating heterogeneous information from diverse sources and disciplines including epidemiology, toxicology, and cell and molecular biology. The causal aspects we discuss focus on these three aspects: drawing sound inferences about causal relations from one or more observational studies; addressing and resolving biases that can affect a single multivariate empirical exposure-response study; and applying the results from these considerations to the microbiological risk management of human health risks and benefits of a ban on antibiotic use in animals, in the context of banning enrofloxacin or macrolides, antibiotics used against bacterial illnesses in poultry, and the effects of such bans on changing the risk of human food-borne campylobacteriosis infections. The purposes of this paper are to describe novel causal methods for assessing empirical causation and inference; exemplify how to deal with biases that routinely arise in multivariate exposure- or dose-response modeling; and provide a simplified discussion of a case study of causal inference using microbial risk analysis as an example. The case study supports the conclusion that the human health benefits from a ban are unlikely to be greater than the excess human health risks that it could create, even when accounting for uncertainty. We conclude that quantitative causal analysis of risks is a preferable to qualitative assessments because it does not involve unjustified loss of information and is sound under the inferential use of risk results by management.

Sonographic assessment of hepatic transplants.

Liver transplantation has become a standard treatment for end-stage liver disease, with survival rates for liver transplant patients increasing steadily. Several imaging techniques are used to evaluate patients for possible complications of liver transplantation. This article focuses on the role of ultrasound and color flow and spectral Doppler in evaluating complications such as fluid collections and vascular or biliary obstructions.

Hastening death: a comparison of two end-of-life decisions.

This study determined the relationship of psychosocial and background variables to elders' end-of-life (EOL) decision preferences. Responding to 5 EOL decision scenarios depicting terminally ill elders, 200 elders aged 60-90 indicated preferences regarding extending life (EL), refusing treatment (RT), and assisted suicide (AS). They were also assessed on religiosity, values, fear of death, locus of control, health, socioeconomic status, and age. Results of multinomial logistic regression indicated that EOL decisions of three groups (favoring EL, favoring RT, and favoring both AS and RT) were significantly influenced by religiosity, value for preservation of life, value for quality of life, fear of death, and locus of control belief. The importance of safeguarding older adults' autonomy in EOL decisions was stressed.

The impact of electron transport on the accuracy of computed dose.

The aim of this work was to investigate the accuracy of dose predicted by a Batho power law correction, and two models which account for electron range: A superposition/convolution algorithm and a Monte Carlo algorithm. The results of these models were compared in phantoms with cavities and low-density inhomogeneities. An idealized geometry was considered with inhomogeneities represented by regions of air and lung equivalent material. Measurements were performed with a parallel plate ionization chamber, thin TLDs (thermoluminescent dosimeters) and film. Dose calculations were done with a generalized Batho model, the Pinnacle collapsed cone convolution model (CCC), and the Peregrine Monte Carlo dose calculation algorithm. Absolute central axis and off axis dose data at various depths relative to interfaces of inhomogeneities were compared. Our results confirm that for a Batho correction, dose errors in the calculated depth dose arise from the neglect of electron transport. This effect increases as the field size decreases, as the density of the inhomogeneity decreases, and with the energy of incident photons. The CCC calculations were closer to measurements than the Batho model, but significant discrepancies remain. Monte Carlo results agree with measurements within the measurement and computational uncertainties.

Patient-dependent beam-modifier physics in Monte Carlo photon dose calculations.

Model pencil-beam on slab calculations are used as well as a series of detailed calculations of photon and electron output from commercial accelerators to quantify level(s) of physics required for the Monte Carlo transport of photons and electrons in treatment-dependent beam modifiers, such as jaws, wedges, blocks, and multileaf collimators, in photon teletherapy dose calculations. The physics approximations investigated comprise (1) not tracking particles below a given kinetic energy, (2) continuing to track particles, but performing simplified collision physics, particularly in handling secondary particle production, and (3) not tracking particles in specific spatial regions. Figures-of-merit needed to estimate the effects of these approximations are developed, and these estimates are compared with full-physics Monte Carlo calculations of the contribution of the collimating jaws to the on-axis depth-dose curve in a water phantom. These figures of merit are next used to evaluate various approximations used in coupled photon/electron physics in beam modifiers. Approximations for tracking electrons in air are then evaluated. It is found that knowledge of the materials used for beam modifiers, of the energies of the photon beams used, as well as of the length scales typically found in photon teletherapy plans, allows a number of simplifying approximations to be made in the Monte Carlo transport of secondary particles from the accelerator head and beam modifiers to the isocenter plane.

The influence of physical activity, socioeconomic status, and ethnicity on the weight status of adolescents.

OBJECTIVE: This study examined the effects of physical activity, television viewing, video game play, socioeconomic status (SES), and ethnicity on body mass index (BMI). RESEARCH METHODS AND PROCEDURES: The sample was 2389 adolescents, 10 to 16 years of age (12.7 +/- 1.0 years); 1240 (52%) females and 1149 (48%) males; 77% white and 23% African American; from rural (77%) and urban (23%) settings. BMI and skinfolds were directly assessed. All other data were obtained from questionnaires. RESULTS: Watching television on non-school days was related to being overweight (p < 0.005). However, when BMI analyses were adjusted for ethnicity and SES, there were no significant effects of television viewing on BMI (p > 0.061). Increased hours of video game play enhanced the risk of being overweight for both genders when analyses were adjusted for ethnicity and SES (p < 0.019). In males, participation in as little as one high-intensity physical activity 3 to 5 days a week decreased the ethnic- and SES-adjusted relative risk of being overweight (RR = 0.646; CI: 0.427 to 0.977). For females, the ethnic- and SES-adjusted relative risk for being overweight was not significantly altered by physical activity. The logistic analyses further indicated the influence of low SES and African American ethnicity overshadowed any direct effect of television or videos. DISCUSSION: Because weight status of male adolescents appears to be more related to exercise habits than to television or video game habits, increased participation in high-intensity exercise appears to be important. For females, neither videos nor exercise habits appear to be related to risk of being overweight. However, ethnicity and SES may be important factors that can influence body weight status, while television viewing may be of some importance. Thus, programs to reduce obesity in female adolescent should focus their efforts in lower SES communities.

Correlated histogram representation of Monte Carlo derived medical accelerator photon-output phase space.

We present a method for condensing the photon energy and angular distributions obtained from Monte Carlo simulations of medical accelerators. This method represents the output as a series of correlated histograms and as such is well-suited for inclusion as the photon-source package for Monte Carlo codes used to determine the dose distributions in photon teletherapy. The method accounts for the isocenter-plane variations of the photon energy spectral distributions with increasing distance from the beam central axis for radiation produced in the bremsstrahlung target as well as for radiation scattered by the various treatment machine components within the accelerator head. Comparison of the isocenter energy fluence computed by this algorithm with that of the underlying full-physics Monte Carlo photon phase space indicates that energy fluence errors are less than 1% of the maximum energy fluence for a range of open-field sizes. Comparison of jaw-edge penumbrae shows that the angular distributions of the photons are accurately reproduced. The Monte Carlo sampling efficiency (the fraction of generated photons which clear the collimator jaws) of the algorithm is approximately 83% for an open 10x10 field, rising to approximately 96% for an open 40x40 field. Data file sizes for a typical medical accelerator, at a given energy, are approximately 150 kB, compared to the 1 GB size of the underlying full-physics phase space file.

Monte Carlo calculations to characterize the source for neutron therapy facilities.

Modern radiation treatment planning for photons includes full 3D modeling of the adsorbed dose distribution, accurate inclusion of the patient anatomy, and consideration of significant changes in material density and composition. Such efforts are founded in an accurate description of the radiation source and the beam delivery system. Modern fast neutron therapy facilities employ highly penetrating beams and isocentric beam delivery. Treatment planning is largely based on analytic models adapted from photon codes and interaction cross sections normalized to macroscopic attenuation. However, the recent PEREGRINE initiative at Lawrence Livermore Laboratory offers the possibility of fully stochastic modeling if the neutron source can be adequately described. In this article we report neutron source modeling of three high energy facilities. Neutron production is based on the intra-nuclear cascade model of the LAHET code while neutron transport through the beam delivery system is managed by MCNP using cross section libraries extended to 100 MeV neutron energy. PEREGRINE is then used to transport the neutron beam through typical phantoms. The resulting neutron sources are in excellent agreement with the limited experimental information and the measured phantom data are well described by the PEREGRINE transport using the LAHET/MCNP determined neutron sources.

Community advisory boards: their role in AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS.

Community-based AIDS research programs were initially federally funded in 1989. Since then, the Terry Beirn Community Programs for Clinical Research on AIDS has mandated that research units develop and maintain community advisory boards to provide advice and communicate community preferences in AIDS research. Seventeen community-based AIDS research units formed community advisory boards (CABs) based on a model developed by the Community Consortium at San Francisco General Hospital. Social workers employed by these AIDS research units surveyed 267 CAB members to ascertain board characteristics and members' perceptions of program activities. Implications for social work and future research are discussed.

Reassessing benzene risks using internal doses and Monte-Carlo uncertainty analysis.

Human cancer risks from benzene have been estimated from epidemiological data, with supporting evidence from animal bioassay data. This article reexamines the animal-based risk assessments using physiologically based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. Internal doses (total benzene metabolites) from oral gavage experiments in mice are well predicted by the PBPK model. Both the data and the PBPK model outputs are also well described by a simple nonlinear (Michaelis-Menten) regression model, as previously used by Bailer and Hoel [Metabolite-based internal doses used in risk assessment of benzene. Environ Health Perspect 82:177-184 (1989)]. Refitting the multistage model family to internal doses changes the maximum-likelihood estimate (MLE) dose-response curve for mice from linear-quadratic to purely cubic, so that low-dose risk estimates are smaller than in previous risk assessments. In contrast to Bailer and Hoel's findings using interspecies dose conversion, the use of internal dose estimates for humans from a PBPK model reduces estimated human risks at low doses. Sensitivity analyses suggest that the finding of a nonlinear MLE dose-response curve at low doses is robust to changes in internal dose definitions and more consistent with epidemiological data than earlier risk models. A Monte-Carlo uncertainty analysis based on maximum-entropy probabilities and Bayesian conditioning is used to develop an entire probability distribution for the true but unknown dose-response function. This allows the probability of a positive low-dose slope to be quantified: It is about 10%. An upper 95% confidence limit on the low-dose slope of excess risk is also obtained directly from the posterior distribution and is similar to previous q1* values. This approach suggests that the excess risk due to benzene exposure may be nonexistent (or even negative) at sufficiently low doses. Two types of biological information about benzene effects--pharmacokinetic and hematotoxic--are examined to test the plausibility of this finding. A framework for incorporating causally relevant biological information into benzene risk assessment is introduced, and it is shown that both pharmacokinetic and hematotoxic models appear to be consistent with the hypothesis that sufficiently low concentrations of inhaled benzene do not create and excess risk.

Assessment of bone ages by the Tanner-Whitehouse method using a computer-aided system.

A computer-aided system to estimate bone age based on Fourier analysis was assessed by reference to the original radiographs used to produce the Tanner-Whitehouse 2 (TW2) standards for the radius, ulna and short finger bones. The computer-aided system involved matching a template of each bone to the scanned image of the radiograph. The computer then generated a stage of bone maturity, individual and total bone scores and a value for bone age. The bone ages assessed by the computer-aided system were no different from the original TW2 reference values, indicating the applicability of the system. The system was used to assess the bone ages of tall Dutch girls, and the results obtained were compared with more traditional assessments made by an experienced rater. For the radiographs from the tall girls, there was good agreement for individual bones between this method and the traditional assessment by the rater, but less agreement for the total 13-bone score and bone age.

Head circumference standards for Irish children.

A cross-sectional study measuring head circumference was performed on 3,344 Irish Children aged from 5 to 19 years. Comparison with other countries showed a slightly larger head circumference than the 1965 British standards produced by Tanner, but significantly smaller than the Ounsted data from Oxford. There was no significant difference between the urban and rural children, but the children of non-manual workers had a significantly larger head than those of manual workers.

Statistical issues in the estimation of assigned shares for carcinogenesis liability.

Congress is currently considering adopting a mathematical formula to assign shares in cancer causation to specific doses of radiation, for use in establishing liability and compensation awards. The proposed formula, if it were sound, would allow difficult problems in tort law and public policy to be resolved by reference to tabulated "probabilities of causation." This article examines the statistical and conceptual bases for the proposed methodology. We find that the proposed formula is incorrect as an expression for "probability and causation," that it implies hidden, debatable policy judgments in its treatment of factor interactions and uncertainties, and that it can not in general be quantified with sufficient precision to be useful. Three generic sources of statistical uncertainty are identified--sampling variability, population heterogeneity, and error propagation--that prevent accurate quantification of "assigned shares." These uncertainties arise whenever aggregate epidemiological or risk data are used to draw causal inferences about individual cases.

Clinical growth standards for Irish children.

A cross-sectional study, measuring height and weight, was performed on a representative sample of 3,509 Irish children aged from 5 to 19 years inclusive. Comparison with other countries showed a significantly later pubertal growth spurt than either the U.K. or the U.S. However, the final adult height and weight are similar to other countries as in the weight-for-height of children aged 5 to 9 years. The urban children are taller than the rural and the higher socio-economic groups are taller than the lower at all ages, but all achieved the same final adult height. Longitudinal tempo-conditional growth standards were constructed based on the Irish cross-sectional and menarche data together with all the available information from longitudinal studies. These charts are similar to those of the U.K., but the use of colours allows more information to be put on the charts, thus making them more suitable for clinical use.

The age of menarche in Irish girls.

PIP: Age at menarche in Ireland is analyzed using data from a representative sample of 2,940 girls aged 9 to 17 drawn from schools in Dublin, Dundalk, Navan, and Portlaoise, of whom some half were urban and half rural residents. The mean age at menarche was 13.52 years. The authors note that this is the latest mean age at menarche recorded for a contemporary European population. No significant differences in age at menarche by place of residence or social class were noted.^ieng