Systems Science for Caribbean Health: the development and piloting of a model for guiding policy on diabetes in the Caribbean.

BACKGROUND: Diabetes is highly prevalent in the Caribbean, associated with a high morbidity and mortality and is a recognised threat to economic and social development. Heads of Government in the Caribbean Community came together in 2007 and declared their commitment to reducing the burden of non-communicable diseases (NCDs), including diabetes, by calling for a multi-sectoral, systemic response. To facilitate the development of effective policies, policymakers are being engaged in the development and use of a system dynamics (SD) model of diabetes for Caribbean countries. METHODS: Previous work on a diabetes SD model from the United States of America (USA) is being adapted to a local context for three countries in the region using input from stakeholders, a review of existing qualitative and quantitative data, and collection of new qualitative data. Three country models will be developed using one-on-one stakeholder engagement and iterative revision. An inter-country model will also be developed following a model-building workshop. Models will be compared to each other and to the USA model. The inter-country model will be used to simulate policies identified as priorities by stakeholders and to develop targets for prevention and control. The model and model-building process will be evaluated by stakeholders and a manual developed for use in other high-burden developing regions. DISCUSSION: SD has been applied with success for health policy development in high-income country settings. The utility of SD in developing countries as an aid to policy decision-making related to NCDs has not been tested. This study represents the first of its kind.

Quantification of the effects of audible rattle and source type on the human response to environmental vibration.

The present research quantifies the influence of source type and the presence of audible vibration-induced rattle on annoyance caused by vibration in residential environments. The sources of vibration considered are railway and the construction of a light rail system. Data were measured in the United Kingdom using a socio-vibration survey (N = 1281). These data are analyzed using ordinal logit models to produce exposure-response relationships describing community annoyance as a function of vibration exposure. The influence of source type and the presence of audible vibration-induced rattle on annoyance are investigated using dummy variable analysis, and quantified using odds-ratios and community tolerance levels. It is concluded that the sample population is more likely to express higher levels of annoyance if the vibration source is construction compared to railway, and if vibration-induced rattle is audible.

The Built Environment and Health in Low- and Middle-Income Countries: a Review on Quantitative Health Impact Assessments.

PURPOSE OF REVIEW: Features and attributes of the built environment (BE) impact positively and negatively on health, especially in cities facing unprecedented urban population growth and mass motorization. A common approach to assess the health impacts of built environment is health impact assessment (HIA), but it is rarely used in low- and middle-income countries (LMICs) where urbanization rates are fastest. This article reviews selected HIA case studies from LMICs and reports the methods and tools used to support further implementation of quantitative HIAs in cities of LMICs. RECENT FINDINGS: In total, 24 studies were reviewed across Algeria, Brazil, China, India, Iran, Kenya, Thailand, Turkey, and Mauritius. HIAs examine specific pathways through which the built environment acts: air pollution, noise, physical activity, and traffic injury. Few HIAs of BE addressed more than one exposure pathway at a time, and most studies focused on air pollution across the sectors of transport and energy. A wide number of tools were used to conduct exposure assessment, and different models were applied to assess health impacts of different exposures. Those HIAs rely on availability of local concentration data and often use models that have set exposure-response functions (ERFs). ERFs were not adapted to local populations except for HIAs conducted in China. HIAs of BE are being successfully conducted in LMICs with a variety of tools and datasets. Scaling and expanding quantitative health impact modeling in LMICs will require further study on data availability, adapted models/tools, low technical capacity, and low policy demand for evidence from modeling studies. As case studies with successful use of evidence from modeling emerge, the uptake of health impact modeling of BE is likely to increase in favor of people and planet.

TROG 14.04: Multicentre Study of Feasibility and Impact on Anxiety of DIBH in Breast Cancer Patients.

AIMS: The aim of TROG 14.04 was to assess the feasibility of deep inspiration breath hold (DIBH) and its impact on radiation dose to the heart in patients with left-sided breast cancer undergoing radiotherapy. Secondary end points pertained to patient anxiety and cost of delivering a DIBH programme. MATERIALS AND METHODS: The study comprised two groups - left-sided breast cancer patients engaging DIBH and right-sided breast cancer patients using free breathing through radiotherapy. The primary end point was the feasibility of DIBH, defined as left-sided breast cancer patients' ability to breath hold for 15 s, decrease in heart dose in DIBH compared with the free breathing treatment plan and reproducibility of radiotherapy delivery using mid-lung distance (MLD) assessed on electronic portal imaging as the surrogate. The time required for treatment delivery, patient-reported outcomes and resource requirement were compared between the groups. RESULTS: Between February and November 2018, 32 left-sided and 30 right-sided breast cancer patients from six radiotherapy centres were enrolled. Two left-sided breast cancer patients did not undergo DIBH (one treated in free breathing as per investigator choice, one withdrawn). The mean heart dose was reduced from 2.8 Gy (free breathing) to 1.5 Gy (DIBH). Set-up reproducibility in the first week of treatment assessed by MLD was 1.88 ± 1.04 mm (average ± 1 standard deviation) for DIBH and 1.59 ± 0.93 mm for free breathing patients. Using a reproducibility cut-off for MLD of 2 mm (1 standard deviation) as per study protocol, DIBH was feasible for 67% of DIBH patients. Radiotherapy delivery using DIBH took about 2 min longer than for free breathing. Anxiety was not significantly different in DIBH patients and decreased over the course of treatment in both groups. CONCLUSION: Although DIBH was shown to require about 2 min longer per treatment slot, it has the potential to reduce heart dose in left-sided breast cancer patients by nearly a half, provided careful assessment of breath hold reproducibility is carried out.

Crucial role of the residue R280 at the F'-G' loop of the human granulocyte/macrophage colony-stimulating factor receptor alpha chain for ligand recognition.

The receptor for granulocyte/macrophage colony-stimulating factor (GM-CSF) is composed of two chains, alpha and betac. Both chains belong to the superfamily of cytokine receptors characterized by a common structural feature, i.e., the presence of at least two fibronectin-like folds in the extracellular domain, which was first identified in the growth hormone receptor. The GM-CSF receptor (GMR)-alpha chain confers low affinity binding only (5-10 nM), whereas the other chain, betac, does not bind GM-CSF by itself but confers high affinity binding when associated with GMR-alpha (25-100 pM). The present study was designed to define the assembly of the GMR complex at the molecular level through site-directed mutagenesis guided by homology modeling with the growth hormone receptor complex. In our three-dimensional model, R280 of GMR-alpha, located in the F'-G' loop and close to the WSSWS motif, is in the vicinity of the ligand Asp112, suggesting the possibility of electrostatic interaction between these two residues. Through site directed mutagenesis, we provide several lines of evidence indicating the importance of electrostatic interaction in ligand-receptor recognition. First, mutagenesis of GMR-alphaR280 strikingly ablated ligand binding in the absence of beta common (betac); ligand binding was restored in the presence of betac with, nonetheless, a significant shift from high (26 pM) toward low affinity (from 2 to 13 nM). The rank order of the dissociation constant for the different GMR-alphaR280 mutations where Lys > Gln > Met > Asp, suggesting the importance of the charge at this position. Second, a mutant GM-CSF with charge reversal mutation at position Asp112 exhibited a 1,000-fold decrease in affinity in receptor binding, whereas charge ablation or conservative mutations were the least affected (10-20-fold). Third, removal of the charge at position R280 of GMR-alpha introduced a 10-fold decrease in the association rate constant and only a 2-fold change in the dissociation rate constant, suggesting that R280 is implicated in ligand recognition, possibly through interaction with Asp112 of GM-CSF. For all R280 mutants, the half-efficient concentrations of GM-CSF required for membrane (receptor binding) to nuclear events (c-fos promoter activation) and cell proliferation (thymidine incorporation) were in the same range, indicating that the threshold for biologic activity is governed mainly by the affinity of ligand-receptor interaction. Furthermore, mutation of other residues in the immediate vicinity of R280 was less drastic. Sequence alignment and modeling of interleukin (IL)-3R and IL-5R identified an arginine residue at the tip of a beta turn in a highly divergent context at the F'-G' loop, close to a conserved structural element, the WSXWS motif, suggesting the possibility of a ligand association mechanism similar to the one described herein for GMR.

The prospects for "personalized medicine" in drug development and drug therapy.

There has been much recent discussion about the advent of "personalized medicine," but controversy exists over its exact definition; how, when, and whether it will be brought about, and what means could be used to measure its attainment. In fact, the concept of "personalized medicine" is a sort of shorthand used to represent the logical next steps in progression of medical science toward greater mechanistic understanding of health, disease, and treatment. This shorthand is attractive to the public because of its intuitive appeal, and irritating to the biomedical community because it glosses over the very real scientific and implementation challenges. This paper evaluates the trajectory and promise of these next steps for the currently problematic states of both drug development and therapy.

Molecular medicine: how, what, and when?

Integrating molecular medicine into clinical practice will create many challenges. But the existing genetic testing paradigm may not be the right model for introducing these new technologies.

Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding.

The human interleukin-3 receptor (IL-3R) is a heterodimer that comprises an IL-3 specific alpha chain (IL-3R alpha) and a common beta chain (beta C) that is shared with the receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5. These receptors belong to the cytokine receptor superfamily, but they are structurally and functionally more related to each other and thus make up a distinct subfamily. Although activation of the normal receptor occurs only in the presence of ligand, the underlying mechanisms are not known. We show here that human IL-3 induces heterodimerization of IL-3R alpha and beta c and that disulfide linkage of these chains is involved in receptor activation but not high-affinity binding. Monoclonal antibodies (MAb) to IL-3R alpha and beta c were developed which immunoprecipitated, in the absence of IL-3, the respective chains from cells labelled with 125I on the cell surface. However, in the presence of IL-3, each MAb immunoprecipitated both IL-3R alpha and beta c. IL-3-induced receptor dimers were disulfide and nondisulfide linked and were dependent on IL-3 interacting with both IL-3R alpha and beta c. In the presence of IL-3 and under nonreducing conditions, MAb to either IL-3R alpha or beta c immunoprecipitated complexes with apparent molecular weights of 215,000 and 245,000 and IL-3R alpha and beta c monomers. Preincubation with iodoacetamide prevented the formation of the two high-molecular-weight complexes without affecting noncovalent dimer formation or high-affinity IL-3 binding. Two-dimensional gel electrophoresis and Western blotting (immunoblotting) demonstrated the presence of both IL-3R alpha and beta c in the disulfide-linked complexes. IL-3 could also be coimmunoprecipitated with anti-IL-3R alpha or anti-beta c MAB, but it was not covalently attached to the receptor. Following IL-3 stimulation, only the disulfide-linked heterodimers exhibited reactivity with antiphosphotyrosine antibodies, with beta c but not IL-3R alpha being the phosphorylated species. A model of IL-3R activation is proposed which may be also applicable to the related GM-CSF and IL-5 receptors.

CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1.

CIB1 (calcium and integrin binding protein 1) is a small intracellular protein with numerous interacting partners, and hence has been implicated in various cellular functions. Recent studies have revealed emerging roles of CIB1 in regulating cancer cell survival and angiogenesis, although the mechanisms involved have remained largely undefined. In investigating the oncogenic function of CIB1, we initially found that CIB1 is widely up-regulated across a diverse range of cancers, with this upregulation frequently correlating with oncogenic mutations of KRas. Consistent with this, we found that ectopic expression of oncogenic KRas and HRas in cells resulted in elevated CIB1 expression. We previously described the Ca2+-myristoyl switch function of CIB1, and its ability to facilitate agonist-induced plasma membrane localisation of sphingosine kinase 1 (SK1), a location where SK1 is known to elicit oncogenic signalling. Thus, we examined the role this may play in oncogenesis. Consistent with these findings, we demonstrated here that over-expression of CIB1 by itself is sufficient to drive localisation of SK1 to the plasma membrane and enhance the membrane-associated enzymatic activity of SK1, as well as its oncogenic signalling. We subsequently demonstrated that elevated levels of CIB1 resulted in full neoplastic transformation, in a manner dependent on SK1. In agreement with our previous findings that SK1 is a downstream mediator of oncogenic signalling by Ras, we found that targeting CIB1 also inhibited neoplastic growth of cells induced by oncogenic Ras, suggesting an important pro-tumorigenic role for CIB1. Thus, we have demonstrated for the first time a role for CIB1 in neoplastic transformation, and revealed a novel mechanism facilitating oncogenic signalling by Ras and SK1.

"Precision" drug development?

The concept of precision medicine has entered broad public consciousness, spurred by a string of targeted drug approvals, highlighted by the availability of personal gene sequences, and accompanied by some remarkable claims about the future of medicine. It is likely that precision medicines will require precision drug development programs. What might such programs look like?

A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Non-Small Cell Lung Cancer.

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analyses. There is much interest in quantifying regulatory approaches to benefit and risk. In this work the use of a quantitative benefit-risk analysis was applied to regulatory decision-making about new drugs to treat advanced non-small cell lung cancer (NSCLC). Benefits and risks associated with 20 US Food and Drug Administration (FDA) decisions associated with a set of candidate treatments submitted between 2003 and 2015 were analyzed. For benefit analysis, the median overall survival (OS) was used where available. When not available, OS was estimated based on overall response rate (ORR) or progression-free survival (PFS). Risks were analyzed based on magnitude (or severity) of harm and likelihood of occurrence. Additionally, a sensitivity analysis was explored to demonstrate analysis of systematic uncertainty. FDA approval decision outcomes considered were found to be consistent with the benefit-risk logic.

Human annoyance, acceptability and concern as responses to vibration from the construction of Light Rapid Transit lines in residential environments.

The aim of this paper is to investigate the use of different self-reported measures for assessing the human response to environmental vibration from the construction of an urban LRT (Light Rapid Transit) system. The human response to environmental stressors such as vibration and noise is often expressed in terms of exposure-response relationships that describe annoyance as a function of the magnitude of the vibration. These relationships are often the basis of noise and vibration policy and the setting of limit values. This paper examines measures other than annoyance by expressing exposure-response relationships for vibration in terms of self-reported concern about property damage and acceptability. The exposure-response relationships for concern about property damage and for acceptability are then compared with those for annoyance. It is shown that concern about property damage occurs at vibration levels well below those where there is any risk of damage. Earlier research indicated that concern for damage is an important moderator of the annoyance induced. Acceptability, on the other hand, might be influenced by both annoyance and concern, as well as by other considerations. It is concluded that exposure-response relationships expressing acceptability as a function of vibration exposure could usefully complement existing relationships for annoyance in future policy decisions regarding environmental vibration. The results presented in this paper are derived from data collected through a socio-vibration survey (N=321) conducted for the construction of an urban LRT in the United Kingdom.

Commentary concerning demonstration of safety and efficacy of investigational anticancer agents in clinical trials.

Expeditious clinical development and approval of new drugs that are beneficial to patients are matters of high priority. There has been a great deal of discussion within the oncology community about what should constitute evidence of effectiveness of new anticancer agents for purposes of drug approval. This commentary is intended to illustrate a variety of end points that can lead to approval of new anticancer agents for specific clinical situations. Although the ultimate hope of antineoplastic therapy is prolongation of life, there are other effects of anticancer drugs that constitute clear clinical benefit and represent evidence of effectiveness. The guiding principle is that the beneficial effects obtained from a new drug should sufficiently outweigh the adverse effects such that the potential risk:benefit ratio achieved by an individual patient is favorable. The assessment of a new drug should flexibly evaluate safety and efficacy in the context of the specific clinical condition being treated. Early discussions with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) are recommended to identify prospectively the end points and trial designs needed to demonstrate effectiveness of a new drug. The general principles discussed will likely apply to the drug approval process for other medical disciplines as well.

Development and validation of an in vivo analysis tool to identify changes in carotid plaque tissue types in serial 3-D ultrasound scans.

We have developed a three-dimensional (3-D) B-mode acquisition system suitable for imaging carotid plaques in vivo. A texture classification system using 157 statistical and textural algorithms, previously developed in our laboratory and shown to predict the contents of in vitro carotid plaques, was applied to in vivo 3-D image sets obtained from patients with both symptomatic and asymptomatic carotid artery plaques. Delineation of plaque boundaries is more difficult using in vivo images than in vitro images of excised plaques embedded in agar. This study has examined inter- and intraobserver variability studies to assess the degree of selectivity of the plaque region-of-interest (ROI) and assess the degree of repeatability for potential use in comparing serial scans. An interobserver limit of agreement of +/-12.9% and an intraobserver limit of repeatability of <2% were obtained. These results show that the plaque ROI selection is subjective, but is repeatable within acceptable limits.

Interaction of GM-CSF and IL-3 with the common beta-chain of their receptors.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL-3) are cytokines active in both normal and abnormal hemopoiesis, inflammation, and immunity. Their biological activity is mediated via receptors that comprise a ligand-specific alpha chain and a beta chain that is common to the GM-CSF, IL-3, and IL-5 receptors. To understand the mechanism of action of GM-CSF and IL-3 in both normal and pathological conditions, we are seeking to define the structural elements required for ligand/receptor and receptor/receptor contact and their role in cellular activation. To this end we have identified a conserved motif in the first helix of GM-CSF, Glu21 that is critical for high affinity binding and biological activity. Charge-reversal mutagenesis of this residue generates a GM-CSF analogue that is devoid of biological activity and can antagonize the activity of wild-type GM-CSF. This probably results from the selective deficiency in interaction with the beta chain of the receptor and suggests that similar antagonists for IL-3 and IL-5 are also feasible. Complementary mutagenesis studies on the receptor beta chain have identified the putative B'-C' loop in the membrane-proximal domain as being critical for the high affinity binding of GM-CSF but not IL-3. Characterization of the specificity of sites of interaction between the ligands and receptors may permit the design of specific or genetic antagonists that may have important therapeutic implications.

Detection of early arterial disease: a study using Doppler waveform analysis.

Laplace transform analysis of arterial Doppler waveforms was examined for its potential in identifying subjects with early, pre-symptomatic arterial disease. Ninety men, aged 45 to 62, and with no history of cardiovascular disease, were selected from a population of 2300 involved in a longitudinal study of risk factors for cardiovascular disease. Forty-nine were selected on the basis of high values of Laplace delta, omega o, or both, and 41 were selected with "normal" values. Three years after initial screening examination, each was examined clinically and by exercise testing for evidence of arterial disease, and the waveform recordings were repeated. In the group with high waveform analysis values initially, 11 of 49 (22%) were found to have signs of arterial disease 3 years later, while among those with lower values only 2 of 41 (5%) had evidence of disease (p less than 0.05). Although variability of results obviates their use in monitoring the progress of individual subjects, this study supports the potential of Doppler waveform analysis for identifying a group of subjects with a high incidence of early arterial disease.

Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization.

The discovery, development, and use of biomarkers for a variety of drug development purposes are areas of tremendous interest and need. Biomarkers can become accepted for use through submission of biomarker data during the drug approval process. Another emerging pathway for acceptance of biomarkers is via the biomarker qualification program developed by the Center for Drug Evaluation and Research (CDER, US Food and Drug Administration). Evidentiary standards are needed to develop and evaluate various types of biomarkers for their intended use and multiple stakeholders, including academia, industry, government, and consortia must work together to help develop this evidence. The article describes various types of biomarkers that can be useful in drug development and evidentiary considerations that are important for qualification. A path forward for coordinating efforts to identify and explore needed biomarkers is proposed for consideration.