A Framework for the Next Generation of Risk Science

Objectives: In 2011, the U.S. Environmental Protection Agency initiated the NexGen project to develop a new paradigm for the next generation of risk science.Methods: The NexGen framework was built on three cornerstones: the availability of new data on toxicity pathways made possible by fundamental advances in basic biology and toxicological science, the incorporation of a population health perspective that recognizes that most adverse health outcomes involve multiple determinants, and a renewed focus on new risk assessment methodologies designed to better inform risk management decision making.Results: The NexGen framework has three phases. Phase I (objectives) focuses on problem formulation and scoping, taking into account the risk context and the range of available risk management decision-making options. Phase II (risk assessment) seeks to identify critical toxicity pathway perturbations using new toxicity testing tools and technologies, and to better characterize risks and uncertainties using advanced risk assessment methodologies. Phase III (risk management) involves the development of evidence-based population health risk management strategies of a regulatory, economic, advisory, community-based, or technological nature, using sound principles of risk management decision making.Conclusions: Analysis of a series of case study prototypes indicated that many aspects of the NexGen framework are already beginning to be adopted in practice.Citation: Krewski D, Westphal M, Andersen ME, Paoli GM, Chiu WA, Al-Zoughool M, Croteau MC, Burgoon LD, Cote I. 2014. A framework for the next generation of risk science. Environ Health Perspect 122:796–805; http://dx.doi.org/10.1289/ehp.1307260     

Socioeconomic Disparities in Telephone-Based Treatment of Tobacco Dependence

Objectives. We examined socioeconomic disparities in tobacco dependence treatment outcomes from a free, proactive telephone counseling quitline.Methods. We delivered cognitive–behavioral treatment and nicotine patches to 6626 smokers and examined socioeconomic differences in demographic, clinical, environmental, and treatment use factors. We used logistic regressions and generalized estimating equations (GEE) to model abstinence and account for socioeconomic differences in the models.Results. The odds of achieving long-term abstinence differed by socioeconomic status (SES). In the GEE model, the odds of abstinence for the highest SES participants were 1.75 times those of the lowest SES participants. Logistic regression models revealed no treatment outcome disparity at the end of treatment, but significant disparities 3 and 6 months after treatment.Conclusions. Although quitlines often increase access to treatment for some lower SES smokers, significant socioeconomic disparities in treatment outcomes raise questions about whether current approaches are contributing to tobacco-related socioeconomic health disparities. Strategies to improve treatment outcomes for lower SES smokers might include novel methods to address multiple factors associated with socioeconomic disparities.In the United States, the prevalence of daily smoking among lower socioeconomic status (SES) groups is 3 to 4 times higher than that of higher SES groups and a leading contributor to socioeconomic health disparities.1–5 Comprehensive tobacco control programs can reduce these disparities by providing all smokers with effective treatment for tobacco dependence; however, significant socioeconomic disparities in treatment outcomes are observed in many treatment settings, raising concerns about contributing to or at least maintaining existing disparities with these approaches.6–14 Treatment delivered through telephone quitlines has become widely available in the United States and the United Kingdom.15 Proactive quitlines attract a large proportion of lower SES smokers16–18 and smokers with different demographic and clinical characteristics than in-person, community-based treatments.16,19,20 Because of their ubiquitous nature and because they appear to be especially accessible and attractive to lower SES smokers,16,17,18 quitlines have the potential to attenuate tobacco-related disparities; however, if quitlines also demonstrate socioeconomic disparities in treatment outcomes, then this would strengthen concerns about current approaches contributing to or maintaining these disparities.SES ideally incorporates the social and economic factors that influence what position individuals or groups hold in a societal structure.21,22 In health research, SES is a broad construct describing relative access to basic resources required to achieve or maintain good health.23,24 Consistent with leading conceptual models of health disparities,23–26 SES is empirically related to smoking cessation through complex reciprocal relations among clinical, environmental, and treatment utilization factors including stress, coping resources, psychological factors, exposure to other smokers, and use of treatment resources.6,27–32Cognitive–behavioral treatment (CBT) provided through proactive quitlines is a practical innovation that attracts a promising number of lower SES smokers.15–17,33 Although not targeted to or tailored for lower SES groups, CBT, when delivered appropriately, addresses individuals’ treatment-related clinical characteristics (e.g., stress, coping, dependence level, motivation, self-efficacy, environmental challenges). Nonetheless, significant disparities have been found in CBT treatment outcomes in many tobacco treatment settings.6–14 Quitlines treat smokers with different characteristics than in-person treatment,16,19,20 however, and thus might not demonstrate the same disparities as in-person CBT treatment.6–13We investigated socioeconomic disparities in tobacco dependence treatment outcomes using data from a proactive quitline in Arkansas in operation from 2005 to 2008. We used statistical modeling of abstinence at the end of treatment (EOT) and 3 and 6 months after treatment to examine the independent contribution of SES to treatment outcomes controlling for other factors. Consistent with findings from community-based treatment, we hypothesized that after accounting for demographic, clinical, environmental, and treatment utilization factors, the lowest SES participants would be least likely to achieve long-term abstinence.     

Weight loss from lifestyle interventions and severity of sleep apnoea: a systematic review and meta-analysis

Background

Excess body weight is a risk factor for obstructive sleep apnoea (OSA). The aim of the systematic review was to establish whether weight loss via lifestyle interventions such as diet and exercise are useful in the treatment of OSA.

Methods

A literature search was conducted between 1980 and February 2012. Systematic reviews and randomised controlled trials (RCTs) with participants who had OSA, were overweight or obese, and who had undergone lifestyle interventions with the aim of improving sleep apnoea were included. Meta analyses were conducted for a subset of RCTs with appropriate data.

Results

Two systematic reviews and eight RCTs were included. Meta-analyses were conducted for four RCTs comparing intensive lifestyle interventions to a control. The overall weighted mean differences for weight change, change in apnoea -hypopnoea index (AHI) and change in oxygen desaturation index of ≥4% were as follows: −13.76 kg (95% confidence interval (CI) −19.21, −-8.32), −16.09 (95% CI −25.64, −6.54) and −14.18 (95% CI −24.23, −4.13), respectively. Although high heterogeneity within the meta analyses, all studies favoured the interventions. Long-term follow-up data from three RCTs suggest that improvements in weight and AHI are maintained for up to 60 months.

Conclusions

Intensive lifestyle interventions are effective in the treatment of OSA, resulting in significant weight loss and a reduction in sleep apnoea severity. Weight loss via intensive lifestyle interventions could be encouraged as a treatment for mild to moderate OSA.     

In vivo light scattering measurements for detection of precancerous conditions of the cervix

OBJECTIVE: To examine the utility of in vivo elastic light scattering measurements to diagnose high grade squamous interepithelial lesions (HSIL) of the cervix. METHODS: A newly developed fiber optic probe was used to measure light transport in the cervical epithelium of 36 patients undergoing standard colposcopy. Both unpolarized and polarized light transport were measured in the visible and near-infrared. Spectroscopic results of 29 patients were compared with histopathology of the measured sites using ROC curves, MANOVA and logistic regression. RESULTS: Three spectroscopic parameters are statistically different for HSIL compared with low-grade lesions and normal tissue. When these three spectroscopic parameters are combined, retrospective sensitivities and specificities for HSIL versus non-HSIL are 100% and 80%, respectively. CONCLUSIONS: Reflectance measurements of elastically scattered light show promise as a non-invasive, real-time method to discriminate HSIL from other abnormalities and normal tissue. These results compare favorably with those obtained by fluorescence alone and by fluorescence combined with light scattering.     

Frequency of Automatic Stimulations in Responsive Vagal Nerve Stimulation in Patients With Refractory Epilepsy

BackgroundIn vagal nerve stimulation (VNS) therapy, the release of VNS model 106 (AspireSR) allowed for responsive VNS (rVNS). rVNS utilizes a cardiac-based seizure detection algorithm to detect seizure-induced tachycardia to trigger additional stimulation. There are some studies suggesting clinical benefits of rVNS over traditional VNS, but the performance and significance of autostimulation mode in clinical practice are poorly understood.ObjectivesTo assess the effect of initiation of rVNS therapy and altered stimulation settings on the number of daily stimulations and energy consumption in VNS therapy and to compare autostimulation performance in different epilepsy types.Materials and MethodsRetrospective follow-up of 30 patients with drug-resistant epilepsy treated with rVNS including 17 new implantations and 13 battery replaces at a single center in Finland. Our data consist of 208 different stimulation periods, that is, episodes with defined stimulation settings and both autostimulation and total stimulation performance-related data along with clinical follow-up.ResultsThe variation in autostimulation frequency was highly dependent on the duration of the OFF-time and autostimulation threshold (p < 0.05). There was a large additional effect of autostimulation mode on therapy time and energy consumption with longer OFF-times, but a minor effect with shorter OFF-times. Significantly more autostimulations were triggered in the temporal lobe and multifocal epilepsies than in extratemporal lobe epilepsies.ConclusionsThe initiation of autostimulation mode in VNS therapy increased the total number of stimulations. Shortening the OFF-time leads to a decreased number and share of automatic activations. Epilepsy type may affect autostimulation activity.     

Actions of recombinant human γ-interferon and tumor necrosis factor α on the proliferation and osteoblastic characteristics of human trabecular bone cells in vitro

Using cultured human osteoblast-like cells, we studied the effects of tumor necrosis factor (TNF) and recombinant human γ-interferon (γ-IFN) on osteoblast growth and function, and demonstrated that TNF stimulated bone cell proliferation and prostaglandin production while inhibiting 1,25-(OH)₂D₃—stimulated alkaline phosphatase activity and osteocalcin release. In contrast, γ-IFN inhibited proliferation and stimulated alkaline phosphatase activity of the cells, while inhibiting 1,25-(OH)₂D₃—stimulated osteocalcin production and having variable effects on the release of prostaglandins, depending on the presence of other factors. Our results suggest that TNF and γ-IFN can act directly on bone-forming cells to affect both their proliferation and their differentiated function, and that changes in the ability of cells to produce these factors in disease states may contribute to alterations in the integrity of connective tissue matrices.     

Comparative effectiveness of screening and prevention strategies among BRCA1/2-affected mutation carriers

Comparative effectiveness research has become an integral part of health care planning in most developed countries. In a simulated cohort of women, aged 30–65, who tested positive for BRCA1 or BRCA2 mutations, we compared outcomes of mammography with and without MRI, prophylactic oophorectomy with and without mastectomy, mastectomy alone, and chemoprevention. Methods: Using Treeage 9.02 software, we developed Markov models with 25,000 Monte Carlo simulations and conducted probabilistic sensitivity analysis. We based mutation penetrance rates, breast and ovarian cancer incidence, and mortality rates, and costs in terms of 2009 dollars, on published studies and data from the Surveillance, Epidemiology, and End Results (SEER) Program and the Centers for Medicare and Medicaid Services. We used preference ratings obtained from mutation carriers and controls to adjust survival for quality of life (QALYs). Results: For BRCA1 mutation carriers, prophylactic oophorectomy at 1,741 per QALY, was more cost effective than both surgeries and dominated all other interventions. For < i > BRCA2 < /i > carriers, prophylactic oophorectomy, at1,741 per QALY, was more cost effective than both surgeries and dominated all other interventions. For BRCA2 carriers, prophylactic oophorectomy, at 4,587 per QALY, was more cost effective than both surgeries. Without quality adjustment, both mastectomy and BSO surgeries dominated all other interventions. In all simulations, preventive surgeries or chemoprevention dominated or were more cost effective than screening because screening modalities were costly. Conclusion: Our analysis suggested that among BRCA1/2 mutation carriers, prophylactic surgery would dominate or be cost effective compared to chemoprevention and screening. Annual screening with MRI and mammography was the most effective strategy because it was associated with the longest quality-adjusted survival, but it was also very expensive.     

ADAM28: A potential oncogene involved in asbestos‐related lung adenocarcinomas

Asbestos‐related lung cancer accounts for 4–12% of all lung cancers worldwide. Since putative mechanisms of carcinogenesis differ between asbestos and tobacco induced lung cancers, tumors induced by the two agents may be genetically distinct. To identify gene expression biomarkers associated with asbestos‐related lung tumorigenicity we performed gene expression array analysis on tumors of 36 patients with primary lung adenocarcinoma, comparing 12 patients with lung asbestos body counts above levels associated with urban dwelling (ARLC‐AC: asbestos‐related lung cancer‐adenocarcinoma) with 24 patients with no asbestos bodies (NARLC‐AC: non‐asbestos related lung cancer‐adenocarcinoma). Genes differentially expressed between ARLC‐AC and NARLC‐AC were identified on fold change and P value, and then prioritized using gene ontology. Candidates included ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D, and PRDX1. Expression of these six genes was technically and biologically replicated by qRT‐PCR in the training set and biologically validated in three independent test sets. ADAM28, encoding a disintegrin and metalloproteinase domain protein that interacts with integrins, was consistently upregulated in ARLC across all four datasets. Further studies are being designed to investigate the possible role of this gene in asbestos lung tumorigenicity, its potential utility as a marker of asbestos related lung cancer for purposes of causal attribution, and its potential as a treatment target for lung cancers arising in asbestos exposed persons. © 2010 Wiley‐Liss, Inc.