Intensity modulated proton therapy (IMPT) can improve dose conformality and better spare normal tissue over passive scattering techniques, but range uncertainties complicate its use, particularly for ...moving targets. We report our early experience with IMPT for thoracic malignancies in terms of motion analysis and management, plan optimization and robustness, and quality assurance.
Thirty-four consecutive patients with lung/mediastinal cancers received IMPT to a median 66 Gy(relative biological equivalence RBE). All patients were able to undergo definitive radiation therapy. IMPT was used when the treating physician judged that IMPT conferred a dosimetric advantage; all patients had minimal tumor motion (<5 mm) and underwent individualized tumor-motion dose-uncertainty analysis and 4-dimensional (4D) computed tomographic (CT)-based treatment simulation and motion analysis. Plan robustness was optimized by using a worst-case scenario method. All patients had 4D CT repeated simulation during treatment.
IMPT produced lower mean lung dose (MLD), lung V5 and V20, heart V40, and esophageal V60 than did IMRT (P<.05) and lower MLD, lung V20, and esophageal V60 than did passive scattering proton therapy (PSPT) (P<.05). D5 to the gross tumor volume and clinical target volume was higher with IMPT than with intensity modulated radiation therapy or PSPT (P<.05). All cases were analyzed for beam-angle-specific motion, water-equivalent thickness, and robustness. Beam angles were chosen to minimize the effect of respiratory motion and avoid previously treated regions, and the maximum deviation from the nominal dose-volume histogram values was kept at <5% for the target dose and met the normal tissue constraints under a worst-case scenario. Patient-specific quality assurance measurements showed that a median 99% (range, 95% to 100%) of the pixels met the 3% dose/3 mm distance criteria for the γ index. Adaptive replanning was used for 9 patients (26.5%).
IMPT using 4D CT-based planning, motion management, and optimization was implemented successfully and met our quality assurance parameters for treating challenging thoracic cancers.
Long-term exposure to ambient air pollution has been associated with premature mortality, but associations at concentrations lower than current annual limit values are uncertain. We analysed ...associations between low-level air pollution and mortality within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE).
In this multicentre longitudinal study, we analysed seven population-based cohorts of adults (age ≥30 years) within ELAPSE, from Belgium, Denmark, England, the Netherlands, Norway, Rome (Italy), and Switzerland (enrolled in 2000–11; follow-up until 2011–17). Mortality registries were used to extract the underlying cause of death for deceased individuals. Annual average concentrations of fine particulate matter (PM2·5), nitrogen dioxide (NO2), black carbon, and tropospheric warm-season ozone (O3) from Europe-wide land use regression models at 100 m spatial resolution were assigned to baseline residential addresses. We applied cohort-specific Cox proportional hazard models with adjustment for area-level and individual-level covariates to evaluate associations with non-accidental mortality, as the main outcome, and with cardiovascular, non-malignant respiratory, and lung cancer mortality. Subset analyses of participants living at low pollutant concentrations (as per predefined values) and natural splines were used to investigate the concentration-response function. Cohort-specific effect estimates were pooled in a random-effects meta-analysis.
We analysed 28 153 138 participants contributing 257 859 621 person-years of observation, during which 3 593 741 deaths from non-accidental causes occurred. We found significant positive associations between non-accidental mortality and PM2·5, NO2, and black carbon, with a hazard ratio (HR) of 1·053 (95% CI 1·021–1·085) per 5 μg/m3 increment in PM2·5, 1·044 (1·019–1·069) per 10 μg/m3 NO2, and 1·039 (1·018–1·059) per 0·5 × 10−5/m black carbon. Associations with PM2·5, NO2, and black carbon were slightly weaker for cardiovascular mortality, similar for non-malignant respiratory mortality, and stronger for lung cancer mortality. Warm-season O3 was negatively associated with both non-accidental and cause-specific mortality. Associations were stronger at low concentrations: HRs for non-accidental mortality at concentrations lower than the WHO 2005 air quality guideline values for PM2·5 (10 μg/m3) and NO2 (40 μg/m3) were 1·078 (1·046–1·111) per 5 μg/m3 PM2·5 and 1·049 (1·024–1·075) per 10 μg/m3 NO2. Similarly, the association between black carbon and non-accidental mortality was highest at low concentrations, with a HR of 1·061 (1·032–1·092) for exposure lower than 1·5× 10−5/m, and 1·081 (0·966–1·210) for exposure lower than 1·0× 10−5/m.
Long-term exposure to concentrations of PM2·5 and NO2 lower than current annual limit values was associated with non-accidental, cardiovascular, non-malignant respiratory, and lung cancer mortality in seven large European cohorts. Continuing research on the effects of low concentrations of air pollutants is expected to further inform the process of setting air quality standards in Europe and other global regions.
Health Effects Institute.
India had the largest number of under-5 deaths of all countries in 2015, with substantial subnational disparities. We estimated national and subnational all-cause and cause-specific mortality among ...children younger than 5 years annually in 2000–15 in India to understand progress made and to consider implications for achieving the Sustainable Development Goal (SDG) child survival targets.
We used a multicause model to estimate cause-specific mortality proportions in neonates and children aged 1–59 months at the state level, with causes of death grouped into pneumonia, diarrhoea, meningitis, injury, measles, congenital abnormalities, preterm birth complications, intrapartum-related events, and other causes. AIDS and malaria were estimated separately. The model was based on verbal autopsy studies representing more than 100 000 neonatal deaths globally and 16 962 deaths among children aged 1–59 months at the subnational level in India. By applying these proportions to all-cause deaths by state, we estimated cause-specific numbers of deaths and mortality rates at the state, regional, and national levels.
In 2015, there were 25·121 million livebirths in India and 1·201 million under-5 deaths (under-5 mortality rate 47·81 per 1000 livebirths). 0·696 million (57·9%) of these deaths occurred in neonates. There were disparities in child mortality across states (from 9·7 deaths Goa to 73·1 deaths Assam per 1000 livebirths) and regions (from 29·7 deaths the south to 63·8 deaths the northeast per 1000 livebirths). Overall, the leading causes of under-5 deaths were preterm birth complications (0·330 million 95% uncertainty range 0·279–0·367; 27·5% of under-5 deaths), pneumonia (0·191 million 0·168–0·219; 15·9%), and intrapartum-related events (0·139 million 0·116–0·165; 11·6%), with cause-of-death distributions varying across states and regions. In states with very high under-5 mortality, infectious-disease-related causes (pneumonia and diarrhoea) were among the three leading causes, whereas the three leading causes were all non-communicable in states with very low mortality. Most states had a slower decline in neonatal mortality than in mortality among children aged 1–59 months. Ten major states must accelerate progress to achieve the SDG under-5 mortality target, while 17 are not on track to meet the neonatal mortality target.
Efforts to reduce vaccine-preventable deaths and to reduce geographical disparities should continue to maintain progress achieved in 2000–15. Enhanced policies and programmes are needed to accelerate mortality reduction in high-burden states and among neonates to achieve the SDG child survival targets in India by 2030.
Bill & Melinda Gates Foundation.
Background Asthma in a mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model in which asthma features persisted for 6 months after cessation of allergen ...exposure. Objective We sought to elucidate factors contributing to the persistence of asthma. Methods We used a combination of immunologic, genetic, microarray, and pharmacologic approaches to dissect the mechanism of asthma persistence. Results Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of recombination-activating gene (Rag1)−/− bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and type 2 innate lymphoid cells (ILC2s) through lethal irradiation and transplantation of Rag2−/− γc−/− bone marrow or blockade of IL-33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed-forward circuits between ILC2s and epithelial cells. Epithelial IL-33 induced ILC2s, a rich source of IL-13. The latter directly induced epithelial IL-33, establishing a positive feedback circuit. IL-33 autoinduced, generating another feedback circuit. IL-13 upregulated IL-33 receptors and facilitated IL-33 autoinduction, thus establishing a feed-forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL-33 and ILC2 levels were increased in the airways of asthmatic patients. IL-33 levels correlated with disease severity. Conclusions We present a critical network of feedback and feed-forward interactions between epithelial cells and ILC2s involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma, they were redundant in maintaining airway hyperreactivity and remodeling.
Malaria-eliminating countries achieved remarkable success in reducing their malaria burdens between 2000 and 2010. As a result, the epidemiology of malaria in these settings has become more complex. ...Malaria is increasingly imported, caused by Plasmodium vivax in settings outside sub-Saharan Africa, and clustered in small geographical areas or clustered demographically into subpopulations, which are often predominantly adult men, with shared social, behavioural, and geographical risk characteristics. The shift in the populations most at risk of malaria raises important questions for malaria-eliminating countries, since traditional control interventions are likely to be less effective. Approaches to elimination need to be aligned with these changes through the development and adoption of novel strategies and methods. Knowledge of the changing epidemiological trends of malaria in the eliminating countries will ensure improved targeting of interventions to continue to shrink the malaria map.
Background Improvement in lung function after macrolide antibiotic therapy has been attributed to reduction in bronchial infection by specific bacteria. However, the airway might be populated by a ...more diverse microbiota, and clinical features of asthma might be associated with characteristics of the airway microbiota present. Objective We sought to determine whether relationships exist between the composition of the airway bacterial microbiota and clinical features of asthma using culture-independent tools capable of detecting the presence and relative abundance of most known bacteria. Methods In this pilot study bronchial epithelial brushings were collected from 65 adults with suboptimally controlled asthma participating in a multicenter study of the effects of clarithromycin on asthma control and 10 healthy control subjects. A combination of high-density 16S ribosomal RNA microarray and parallel clone library-sequencing analysis was used to profile the microbiota and examine relationships with clinical measurements. Results Compared with control subjects, 16S ribosomal RNA amplicon concentrations (a proxy for bacterial burden) and bacterial diversity were significantly higher among asthmatic patients. In multivariate analyses airway microbiota composition and diversity were significantly correlated with bronchial hyperresponsiveness. Specifically, the relative abundance of particular phylotypes, including members of the Comamonadaceae, Sphingomonadaceae, Oxalobacteraceae, and other bacterial families were highly correlated with the degree of bronchial hyperresponsiveness. Conclusion: The composition of bronchial airway microbiota is associated with the degree of bronchial hyperresponsiveness among patients with suboptimally controlled asthma. These findings support the need for further functional studies to examine the potential contribution of members of the airway microbiota in asthma pathogenesis.
The nasal methylome and childhood atopic asthma Yang, Ivana V., PhD; Pedersen, Brent S., PhD; Liu, Andrew H., MD ...
Journal of allergy and clinical immunology,
05/2017, Volume:
139, Issue:
5
Journal Article
Peer reviewed
Open access
Background Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic ...asthma. Objective We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. Methods We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12). Results We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively ( P < 2.8 × 10−6 for differentially methylated regions and P < 7.8 × 10−10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients. Conclusions Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.
Objective The purpose of this study was to evaluate the relationship of left ventricular (LV) mass and geometry measured with cardiac magnetic resonance imaging (MRI) to incident cardiovascular ...events in the MESA (Multi-Ethnic Study of Atherosclerosis) study. Background MRI is highly accurate for evaluation of heart size and structure and has not previously been used in a large epidemiologic study to predict cardiovascular events. Methods A total of 5,098 participants in the MESA study underwent cardiac MRI at the baseline examination and were followed up for a median of 4 years. Cox proportional hazard models were constructed to predict the end points of coronary heart disease (CHD), stroke, and heart failure (HF) after adjustment for cardiovascular risk factors. Results A total of 216 incident events were observed during the follow-up period. In adjusted models, the end points of incident CHD and stroke were positively associated with increased LV mass-to-volume ratio (CHD, hazard ratio HR: 2.1 per g/ml, p = 0.02; stroke, HR: 4.2 per g/ml, p = 0.005). In contrast, LV mass showed the strongest association with incident HF events (HR: 1.4 per 10% increment, p < 0.0001). The HF events occurred primarily in participants with LV hypertrophy, that is, ≥95th percentile of LV mass (HR: 8.6, 95% confidence interval: 3.7 to 19.9, reference group <50th percentile of LV mass). Conclusions The LV size was related to incident HF, stroke, and CHD in this multiethnic cohort. Whereas body size-adjusted LV mass alone predicted incident HF, concentric ventricular remodeling predicted incident stroke and CHD.
Summary Background Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although ...Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. Methods We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. Findings Associations exceeding the genome-wide significance threshold (p<5 × 10−8 ) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1 ) having the strongest association with NKTCL susceptibility (p=4·21 × 10−19 , odds ratio OR 1·84 95% CI 1·61–2·11 in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10−14 ). This association is distinct from MHC associations with Epstein-Barr virus infection. Interpretation To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. Funding Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).
Summary Background Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk ...for complications are not available, and the effect of treatment on risk is unknown. Methods We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. Findings Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51–82) and specificity of 63% (55–71), with a negative predictive value of 95% (94–97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio HR 0·30, 95% CI 0·10–0·89; p=0·0296) but not stricturing complication (1·13, 0·51–2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12–2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. Interpretation Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. Funding Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.