Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs

Linking Microscopic Spatial Patterns of Tissue Destruction in Emphysema to Macroscopic Decline in Stiffness Using a 3D Computational Model

Pulmonary emphysema is a connective tissue disease characterized by the progressive destruction of alveolar walls leading to airspace enlargement and decreased elastic recoil of the lung. However, the relationship between microscopic tissue structure and decline in stiffness of the lung is not well understood. In this study, we developed a 3D computational model of lung tissue in which a pre-strained cuboidal block of tissue was represented by a tessellation of space filling polyhedra, with each polyhedral unit-cell representing an alveolus. Destruction of alveolar walls was mimicked by eliminating faces that separate two polyhedral either randomly or in a spatially correlated manner, in which the highest force bearing walls were removed at each step. Simulations were carried out to establish a link between the geometries that emerged and the rate of decline in bulk modulus of the tissue block. The spatially correlated process set up by the force-based destruction lead to a significantly faster rate of decline in bulk modulus accompanied by highly heterogeneous structures than the random destruction pattern. Using the Karhunen-Loève transformation, an estimator of the change in bulk modulus from the first four moments of airspace cell volumes was setup. Simulations were then obtained for tissue destruction with different idealized alveolar geometry, levels of pre-strain, linear and nonlinear elasticity assumptions for alveolar walls and also mixed destruction patterns where both random and force-based destruction occurs simultaneously. In all these cases, the change in bulk modulus from cell volumes was accurately estimated. We conclude that microscopic structural changes in emphysema and the associated decline in tissue stiffness are linked by the spatial pattern of the destruction process

Measuring Fluorescent Dye in the Bubbly and Sediment-Laden Surfzone

Decisions about recreational beach closures would be enhanced if better estimates of surfzone contaminant transport and dilution were available. In situ methods for measuring fluorescent Rhodamine WT dye tracer in the surfzone are presented, increasing the temporal and spatial resolution over previous surfzone techniques. Bubbles and sand suspended by breaking waves in the surfzone interfere with in situ optical fluorometer dye measurements, increasing the lower bound for dye detection (≈ 1 ppb) and reducing (quenching) measured dye concentrations. Simultaneous turbidity measurements are used to estimate the level of bubble and sand interference and correct dye estimates. After correction, root-mean-square dye concentration errors are estimated to be < 5% of dye concentration magnitude, thus demonstrating the viability of in situ surfzone fluorescent dye measurements. The surfzone techniques developed here may be applicable to other environments with high bubble and sand concentrations (e.g., cascading rivers and streams)

ATG5 is essential for ATG8-dependent autophagy and mitochondrial homeostasis in Leishmania major

Macroautophagy has been shown to be important for the cellular remodelling required for Leishmania differentiation. We now demonstrate that L. major contains a functional ATG12-ATG5 conjugation system, which is required for ATG8-dependent autophagosome formation. Nascent autophagosomes were found commonly associated with the mitochondrion. L. major mutants lacking ATG5 (Δatg5) were viable as promastigotes but were unable to form autophagosomes, had morphological abnormalities including a much reduced flagellum, were less able to differentiate and had greatly reduced virulence to macrophages and mice. Analyses of the lipid metabolome of Δatg5 revealed marked elevation of phosphatidylethanolamines (PE) in comparison to wild type parasites. The Δatg5 mutants also had increased mitochondrial mass but reduced mitochondrial membrane potential and higher levels of reactive oxygen species. These findings indicate that the lack of ATG5 and autophagy leads to perturbation of the phospholipid balance in the mitochondrion, possibly through ablation of membrane use and conjugation of mitochondrial PE to ATG8 for autophagosome biogenesis, resulting in a dysfunctional mitochondrion with impaired oxidative ability and energy generation. The overall result of this is reduced virulence

Estimation of airway obstruction using oximeter plethysmograph waveform data

BACKGROUND: Validated measures to assess the severity of airway obstruction in patients with obstructive airway disease are limited. Changes in the pulse oximeter plethysmograph waveform represent fluctuations in arterial flow. Analysis of these fluctuations might be useful clinically if they represent physiologic perturbations resulting from airway obstruction. We tested the hypothesis that the severity of airway obstruction could be estimated using plethysmograph waveform data. METHODS: Using a closed airway circuit with adjustable inspiratory and expiratory pressure relief valves, airway obstruction was induced in a prospective convenience sample of 31 healthy adult subjects. Maximal change in airway pressure at the mouthpiece was used as a surrogate measure of the degree of obstruction applied. Plethysmograph waveform data and mouthpiece airway pressure were acquired for 60 seconds at increasing levels of inspiratory and expiratory obstruction. At each level of applied obstruction, mean values for maximal change in waveform area under the curve and height as well as maximal change in mouth pressure were calculated for sequential 7.5 second intervals. Correlations of these waveform variables with mouth pressure values were then performed to determine if the magnitude of changes in these variables indicates the severity of airway obstruction. RESULTS: There were significant relationships between maximal change in area under the curve (P < .0001) or height (P < 0.0001) and mouth pressure. CONCLUSION: The findings suggest that mathematic interpretation of plethysmograph waveform data may estimate the severity of airway obstruction and be of clinical utility in objective assessment of patients with obstructive airway diseases

Evaluation of a cervical cancer screening program based on HPV testing and LLETZ excision in a low resource setting

We conducted studies in Vanuatu to evaluate potential screening and treatment strategies to assist with control of cervical cancer. In a pilot study of 496 women, visual inspection and cytology were evaluated as screening tests for detection of CIN 2 or worse (CIN2+), observed in 21 of 206 subjects biopsied on the basis of abnormal visual inspection or cytology. Sensitivity of visual inspection with Lugol's Iodine for detection of CIN2+ on biopsy was 0.63, specificity was 0.32, and the positive predictive value was 0.09. For HSIL cytology, sensitivity was 0.99, specificity was 0.77, and the positive predictive value was 0.88. HSIL cytology was significantly more sensitive and had a significantly higher PPV for CIN 2+ than visual inspection (

Peripheral nervous system manifestations in a Sandhoff disease mouse model: nerve conduction, myelin structure, lipid analysis

<p>Abstract</p> <p>Background</p> <p>Sandhoff disease is an inherited lysosomal storage disease caused by a mutation in the gene for the β-subunit (<it>Hexb </it>gene) of β-hexosaminidase A (αβ) and B (ββ). The β-subunit together with the GM2 activator protein catabolize ganglioside GM2. This enzyme deficiency results in GM2 accumulation primarily in the central nervous system. To investigate how abnormal GM2 catabolism affects the peripheral nervous system in a mouse model of Sandhoff disease (<it>Hexb-/-</it>), we examined the electrophysiology of dissected sciatic nerves, structure of central and peripheral myelin, and lipid composition of the peripheral nervous system.</p> <p>Results</p> <p>We detected no significant difference in signal impulse conduction velocity or any consistent change in the frequency-dependent conduction slowing and failure between freshly dissected sciatic nerves from the <it>Hexb</it>+/- and <it>Hexb</it>-/- mice. The low-angle x-ray diffraction patterns from freshly dissected sciatic and optic nerves of <it>Hexb</it>+/- and <it>Hexb</it>-/- mice showed normal myelin periods; however, <it>Hexb</it>-/- mice displayed a ~10% decrease in the relative amount of compact optic nerve myelin, which is consistent with the previously established reduction in myelin-enriched lipids (cerebrosides and sulfatides) in brains of <it>Hexb-/- </it>mice. Finally, analysis of lipid composition revealed that GM2 content was present in the sciatic nerve of the <it>Hexb</it>-/- mice (undetectable in <it>Hexb</it>+/-).</p> <p>Conclusion</p> <p>Our findings demonstrate the absence of significant functional, structural, or compositional abnormalities in the peripheral nervous system of the murine model for Sandhoff disease, but do show the potential value of integrating multiple techniques to evaluate myelin structure and function in nervous system disorders.</p

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Unhealthy Gambling Amongst New Zealand Secondary School Students: An Exploration of Risk and Protective Factors

This study sought to determine the prevalence of gambling and unhealthy gambling behaviour and describe risk and protective factors associated with these behaviours amongst a nationally representative sample of New Zealand secondary school students (n = 8,500). Factor analysis and item response theory were used to develop a model to provide a measure of ‘unhealthy gambling’. Logistic regressions and multiple logistic regression models were used to investigate associations between unhealthy gambling behaviour and selected outcomes. Approximately one-quarter (24.2 %) of students had gambled in the last year, and 4.8 % had two or more indicators of unhealthy gambling. Multivariate analyses found that unhealthy gambling was associated with four main factors: more accepting attitudes towards gambling (pp = 0.0061); being worried about and/or trying to cut down on gambling (p p = 0.0009). Unhealthy gambling is a significant health issue for young people in New Zealand. Ethnic and social inequalities were apparent and these disparities need to be addressed