Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE.

PURPOSE: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME). DESIGN: Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years. PARTICIPANTS: Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography. METHODS: Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary. MAIN OUTCOME MEASURES: The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24. RESULTS: Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group. CONCLUSIONS: The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references

Polycyclic aromatic hydrocarbon exposure, obesity and childhood asthma in an urban cohort

Background: Exposure to traffic-related air pollutants, including polycyclic aromatic hydrocarbons (PAHs) from traffic emissions and other combustion sources, and childhood obesity, have been implicated as risk factors for developing asthma. However, the interaction between these two on asthma among young urban children has not been studied previously. Methods: Exposure to early childhood PAHs was measured by two week residential indoor monitoring at age 5–6 years in the Columbia Center for Children's Environmental Health birth cohort (n=311). Semivolatile [e.g., methylphenanthrenes] and nonvolatile [e.g., benzo(a)pyrene] PAHs were monitored. Obesity at age 5 was defined as a body mass index (BMI) greater than or equal to the 95th percentile of the year 2000 age- and sex-specific growth charts (Center for Disease Control). Current asthma and recent wheeze at ages 5 and 7 were determined by validated questionnaires. Data were analyzed using a modified Poisson regression in generalized estimating equations (GEE) to estimate relative risks (RR), after adjusting for potential covariates. Results: Neither PAH concentrations or obesity had a main effect on asthma or recent wheeze. In models stratified by presence/absence of obesity, a significant positive association was observed between an interquartile range (IQR) increase in natural log-transformed 1-methylphenanthrene (RR [95% CI]: 2.62 [1.17–5.88] with IQRln=0.76), and 9-methylphenanthrene (2.92 [1.09–7.82] with IQRln=0.73) concentrations and asthma in obese children (n=63). No association in non-obese (n=248) children was observed at age 5 (Pinteraction<0.03). Similar associations were observed for 3-methylphenanthrene, 9-methylphenanthrene, and 3,6-dimethylphenanthrene at age 7. Conclusions: Obese young children may be more likely to develop asthma in association with greater exposure to PAHs, and methylphenanthrenes in particular, than non-obese children

Early-life cockroach allergen and polycyclic aromatic hydrocarbon exposures predict cockroach sensitization among inner-city children

Background: Sensitization to cockroach is one of the strongest identified risk factors for greater asthma morbidity in low-income urban communities; however, the timing of exposures relevant to the development of sensitization has not been elucidated fully. Furthermore, exposure to combustion byproducts, including polycyclic aromatic hydrocarbons (PAHs), can augment the development of allergic sensitization. Objective: We sought to test the hypotheses that domestic cockroach allergen measured prenatally would predict cockroach sensitization in early childhood and that this association would be greater for children exposed to higher PAH concentrations. Methods: Dominican and African American pregnant women living in New York City were enrolled. In the third trimester expectant mothers wore personal air samplers for measurement of 8 nonvolatile PAHs and the semivolatile PAH pyrene, and dust was collected from homes for allergen measurement. Glutathione-S-transferase μ 1 (GSTM1) gene polymorphisms were measured in children. Allergen-specific IgE levels were measured from the children at ages 2, 3, 5, and 7 years. Results: Bla g 2 in prenatal kitchen dust predicted cockroach sensitization at the ages of 5 to 7 years (adjusted relative risk [RR], 1.15; P = .001; n = 349). The association was observed only among children with greater than (RR, 1.22; P = .001) but not less than (RR, 1.07; P = .24) the median sum of 8 nonvolatile PAH levels. The association was most pronounced among children with higher PAH levels and null for the GSTM1 gene (RR, 1.54; P = .001). Conclusions: Prenatal exposure to cockroach allergen was associated with a greater risk of allergic sensitization. This risk was increased by exposure to nonvolatile PAHs, with children null for the GSTM1 mutation particularly vulnerable

Heat kernel regularization of the effective action for stochastic reaction-diffusion equations

The presence of fluctuations and non-linear interactions can lead to scale dependence in the parameters appearing in stochastic differential equations. Stochastic dynamics can be formulated in terms of functional integrals. In this paper we apply the heat kernel method to study the short distance renormalizability of a stochastic (polynomial) reaction-diffusion equation with real additive noise. We calculate the one-loop {\emph{effective action}} and its ultraviolet scale dependent divergences. We show that for white noise a polynomial reaction-diffusion equation is one-loop {\emph{finite}} in $d=0$ and $d=1$, and is one-loop renormalizable in $d=2$ and $d=3$ space dimensions. We obtain the one-loop renormalization group equations and find they run with scale only in $d=2$.Comment: 21 pages, uses ReV-TeX 3.

Personalized Exposure Assessment: Promising Approaches for Human Environmental Health Research

New technologies and methods for assessing human exposure to chemicals, dietary and lifestyle factors, infectious agents, and other stressors provide an opportunity to extend the range of human health investigations and advance our understanding of the relationship between environmental exposure and disease. An ad hoc Committee on Environmental Exposure Technology Development was convened to identify new technologies and methods for deriving personalized exposure measurements for application to environmental health studies. The committee identified a “toolbox” of methods for measuring external (environmental) and internal (biologic) exposure and assessing human behaviors that influence the likelihood of exposure to environmental agents. The methods use environmental sensors, geographic information systems, biologic sensors, toxicogenomics, and body burden (biologic) measurements. We discuss each of the methods in relation to current use in human health research; specific gaps in the development, validation, and application of the methods are highlighted. We also present a conceptual framework for moving these technologies into use and acceptance by the scientific community. The framework focuses on understanding complex human diseases using an integrated approach to exposure assessment to define particular exposure–disease relationships and the interaction of genetic and environmental factors in disease occurrence. Improved methods for exposure assessment will result in better means of monitoring and targeting intervention and prevention programs

Using Routinely Collected Administrative Data in Public Health Research: Geocoding Alcohol Outlet Data

We describe our process of geocoding alcohol outlets to create a national longitudinal exposure dataset for Wales, United Kingdom from 2006 to 2011. We investigated variation in the availability of data items and the quality of alcohol outlet addresses held within unitary authorities. We used a standard geocoding method augmented with a manual matching procedure to achieve a fully spatially referenced dataset. We found higher quality addresses are held for outlets based in urban areas, resulting in the automatic geocoding of 68 % of urban outlets, compared to 48 % in rural areas. Missing postcodes and a lack of address structure contributed to a lower geocoding proportion. An urban rural bias was removed with the development of a manual matching procedure. Only one-half of the unitary authorities provided data on on/off sales and opening times, which are important availability factors. The resulting outlet dataset is suitable for contributing to the evidence-base of alcohol availability and alcohol-related harm. Local government should be encouraged to use standardised data fields, including addresses, to enable accurate geocoding of alcohol outlets and facilitate research that aims to prevent alcohol-related harm. Standardising data collection would enable efficient secondary data reuse using record linkage techniques, allowing the retrospective creation and evaluation of population-based natural experiments to provide evidence for policy and practice