Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies

Background: Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions. Methods and Findings: We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40–69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking. Conclusions: These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries

Development of a first generation perfusion process and medium for continuous processing based on existing fed-batch platform media

Process intensification leveraging perfusion offers tremendous potential for yield improvement over fed-batch processes for the production of monoclonal antibodies. In the context of continuous processing, the goal is to achieve highly intensified perfusion processes that allow substantial footprint reduction and enable flexible adaptation in new facilities. However developing a perfusion process and medium without prior technology requires leveraging the existing fed-batch platform knowledge. Evolving a medium for perfusion relies on designing suitable mixtures of basal and feed media that serve as adequate starting points for development. Focus on optimization of the medium to decrease byproduct waste, reduce unnecessary cell growth and enhance specific productivity is critical. Doing so would allow a more robust and controlled process, and allow steady-state to be more attainable which will aid in maintaining consistent product quality for continuous processing. Moreover, reducing medium utilization hence the ability to operate under lower cell specific perfusion rate was important in order to have a more economical and nimble process. In order to overcome the conventional perfusion medium bottlenecks of equipment capacity, liquid handling, transfer and storage, a different strategy to managing large bulk volume had to be undertaken in order to make fit for an existing small pilot plant. The approach to establishing a first generation perfusion process starting from a fed-batch platform will be shared. Examples demonstrating continuous perfusion and volumetric productivity of \u3e 1 g/L-day under low CSPR will be discussed

From development to implementation with a fully integrated downstream bioprocess

Boehringer Ingelheim and Pfizer have developed a unique continuous bioprocess consisting of a short duration perfusion upstream and fully integrated downstream. The process is designed to generate at least 1 kg of material from a 100 L bioreactor in approximate 2 weeks. The upstream strategy utilizes a non-steady state, short duration perfusion process to achieve volumetric productivities ranging from 0.5 to 4 g/L/day. This creates a unique challenge for the downstream process as the titer and impurity load change over the duration of the culture. To accommodate upstream, a fully integrated downstream process was created using a combination of traditional batch unit operations and continuous bioprocessing. The system design includes a pair of small proteins A columns operated consecutively, a continuous low pH inactivation chamber (cVI), an anion exchange chromatography column, a single pass tangential flow filter, a virus filter and batch UFDF. The key to the system is three distinct operation modes including continuous, periodic and batch phases. The resulting hybrid system provides flexible and robust downstream processing of the continuous perfusion bioreactor. We have successfully used this new downstream process at the predicted manufacturing scale to generate clinical quality drug substance for multiple monoclonal antibodies. With the success of the new integrated system, our team is shifting its focus to implementation on a clinical program. A key element of the ongoing work is to establish the control and robustness of novel elements of our process such as confirming that the critical pH has been achieved during cVI and demonstrating robust impurity removal for dynamic loading on an AEX polishing step. In this talk, we will explain our approach to integrated continuous downstream processing and our strategy for future implementation. Data from at-scale demonstration runs will show the robustness of the process over a wide range of loading conditions. This will include product quality data including HCP, DNA, charge variants and aggregate removal that is consistent with batch processes. Process data will show the control and robustness of the approach

Balancing continuous, integrated, and batch processing

We are building a new disposable manufacturing system to support the development and manufacturing of mAb and mAb-related products. We have made choices that are different than many others in the field of continuous and integrated processing. These choices avoid many misperceptions about continuous processing, are consistent with a staged approach to implementation, and facilitate manufacturing in either large-scale disposable or stainless manufacturing facilities. We have avoided the use of long-term steady-state perfusion. This mode of perfusion suffers from long development times, long manufacturing duration, extended Process Performance Qualification, large media consumption and perceived concerns about product quality variability and contamination. The system uses a short duration (\u3c15 days) non-steady state perfusion with perfusion rates as low as 0.3 bioreactor volumes per day. On-line UPLC is used to monitor product titer and quality. As a consequence of non-steady state perfusion operation, the integrated downstream is capable of handling day to day variability of 0.5g/L/day to 4g/L/day. The downstream avoids the use of SMB or PCC; rather, it integrates two batch chromatographic steps, a continuous virus inactivation step, and avoids in-process pooling. The product is stored after the second chromatography step for the duration of the batch. When the batch is complete, the pooled product is batched through a virus reduction filter and UFDF to make the bulk drug substance. Running these last two processes on the entire product pool at once allows an easy definition of a batch, without worry about pooling drug substance with different product quality profiles. The result is an integrated, semi-continuous manufacturing process that mitigates many of the concerns felt by the batch-processing community

Projections of Global Mortality and Burden of Disease from 2002 to 2030

BACKGROUND: Global and regional projections of mortality and burden of disease by cause for the years 2000, 2010, and 2030 were published by Murray and Lopez in 1996 as part of the Global Burden of Disease project. These projections, which are based on 1990 data, continue to be widely quoted, although they are substantially outdated; in particular, they substantially underestimated the spread of HIV/AIDS. To address the widespread demand for information on likely future trends in global health, and thereby to support international health policy and priority setting, we have prepared new projections of mortality and burden of disease to 2030 starting from World Health Organization estimates of mortality and burden of disease for 2002. This paper describes the methods, assumptions, input data, and results. METHODS AND FINDINGS: Relatively simple models were used to project future health trends under three scenarios—baseline, optimistic, and pessimistic—based largely on projections of economic and social development, and using the historically observed relationships of these with cause-specific mortality rates. Data inputs have been updated to take account of the greater availability of death registration data and the latest available projections for HIV/AIDS, income, human capital, tobacco smoking, body mass index, and other inputs. In all three scenarios there is a dramatic shift in the distribution of deaths from younger to older ages and from communicable, maternal, perinatal, and nutritional causes to noncommunicable disease causes. The risk of death for children younger than 5 y is projected to fall by nearly 50% in the baseline scenario between 2002 and 2030. The proportion of deaths due to noncommunicable disease is projected to rise from 59% in 2002 to 69% in 2030. Global HIV/AIDS deaths are projected to rise from 2.8 million in 2002 to 6.5 million in 2030 under the baseline scenario, which assumes coverage with antiretroviral drugs reaches 80% by 2012. Under the optimistic scenario, which also assumes increased prevention activity, HIV/AIDS deaths are projected to drop to 3.7 million in 2030. Total tobacco-attributable deaths are projected to rise from 5.4 million in 2005 to 6.4 million in 2015 and 8.3 million in 2030 under our baseline scenario. Tobacco is projected to kill 50% more people in 2015 than HIV/AIDS, and to be responsible for 10% of all deaths globally. The three leading causes of burden of disease in 2030 are projected to include HIV/AIDS, unipolar depressive disorders, and ischaemic heart disease in the baseline and pessimistic scenarios. Road traffic accidents are the fourth leading cause in the baseline scenario, and the third leading cause ahead of ischaemic heart disease in the optimistic scenario. Under the baseline scenario, HIV/AIDS becomes the leading cause of burden of disease in middle- and low-income countries by 2015. CONCLUSIONS: These projections represent a set of three visions of the future for population health, based on certain explicit assumptions. Despite the wide uncertainty ranges around future projections, they enable us to appreciate better the implications for health and health policy of currently observed trends, and the likely impact of fairly certain future trends, such as the ageing of the population, the continued spread of HIV/AIDS in many regions, and the continuation of the epidemiological transition in developing countries. The results depend strongly on the assumption that future mortality trends in poor countries will have a relationship to economic and social development similar to those that have occurred in the higher-income countries

Omega-3 Fatty Acid Supplementation Appears to Attenuate Particulate Air Pollution-Induced Cardiac Effects and Lipid Changes in Healthy Middle-Aged Adults

BACKGROUND: Air pollution exposure has been associated with adverse cardiovascular health effects. Findings of a recent epidemiological study suggest that omega-3 fatty acid (fish oil) supplementation blunted cardiac responses to air pollution exposure. OBJECTIVES: We conducted a randomized, controlled exposure study to evaluate the efficacy of fish oil supplements in attenuating adverse cardiac effects of exposure to concentrated ambient fine and ultrafine particulate matter (CAP). METHODS: Twenty-nine healthy middle-aged participants (mean 58 ± 1 years of age) were supplemented in a randomized, double-blinded manner with 3 g/day of either fish oil or olive oil for 4 weeks before sequential chamber exposure to filtered air and CAP (mean mass concentration 278 ± 19 μg/m3) for 2 hr. Cardiac responses were assessed by comparing time and frequency domain changes in heart rate variability (HRV) and electrocardiographic repolarization changes measured before, immediately after, and 20 hr after exposure. Changes in plasma lipids were also evaluated at these time points. RESULTS: Fish oil supplementation appeared to attenuate CAP-induced reductions in high-frequency/low-frequency ratio, as well as elevations in normalized low-frequency HRV and prolongation of the QT interval corrected for heart rate (QTc). Very low-density lipoprotein and triglyceride concentrations increased significantly immediately after exposure to CAP in participants supplemented with olive oil, but not in those supplemented with fish oil. CONCLUSIONS: Exposure of healthy middle-aged adults to CAP for 2 hr induced acute cardiac and lipid changes after supplementation with olive oil, but not fish oil. Our findings suggest that omega-3 fatty acid supplements offer protection against the adverse cardiac and lipid effects associated with air pollution exposure

A Simple HEPA Filtering Facepiece

Shortages of efficient filtering facepiece respirators leave the public vulnerable to transmission of infectious diseases in small particle aerosols. This study demonstrates that a high-filtration-efficiency facepiece capable of filtering out >95% of 0.05μm particles while being worn can be simply produced with available materials

Association between respiratory tract diseases and secondhand smoke exposure among never smoking flight attendants: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Little is known about long-term adverse health consequences experienced by flight attendants exposed to secondhand smoke (SHS) during the time smoking was allowed on airplanes. We undertook this study to evaluate the association between accumulated flight time in smoky airplane cabins and respiratory tract diseases in a cohort of never smoking flight attendants.</p> <p>Methods</p> <p>We conducted a mailed survey in a cohort of flight attendants. Of 15,000 mailed questionnaires, 2053 (14%) were completed and returned. We excluded respondents with a personal history of smoking (n = 748) and non smokers with a history of respiratory tract diseases before the age of 18 years (n = 298). The remaining 1007 respondents form the study sample.</p> <p>Results</p> <p>The overall study sample was predominantly white (86%) and female (89%), with a mean age of 54 years. Overall, 69.7% of the respondents were diagnosed with at least one respiratory tract disease. Among these respondents, 43.4% reported a diagnosis of sinusitis, 40.3% allergies, 30.8% bronchitis, 23.2% middle ear infections, 13.6% asthma, 13.4% hay fever, 12.5% pneumonia, and 2.0% chronic obstructive pulmonary disease. More hours in a smoky cabin were observed to be significantly associated with sinusitis (OR = 1.21; p = 0.024), middle ear infections (OR = 1.30; p = 0.006), and asthma (OR = 1.26; p = 0.042).</p> <p>Conclusion</p> <p>We observed a significant association between hours of smoky cabin exposure and self-reported reported sinusitis, middle ear infections, and asthma. Our findings suggest a dose-response between duration of SHS exposure and diseases of the respiratory tract. Our findings add additional evidence to the growing body of knowledge supporting the need for widespread implementation of clean indoor air policies to decrease the risk of adverse health consequences experienced by never smokers exposed to SHS.</p

Dietary Supplementation with Olive Oil or Fish Oil and Vascular Effects of Concentrated Ambient Particulate Matter Exposure in Human Volunteers

BackgroundExposure to ambient particulate matter (PM) induces endothelial dysfunction, a risk factor for cardiovascular disease. Olive oil (OO) and fish oil (FO) supplements have beneficial effects on endothelial function.ObjectiveIn this study we evaluated the potential efficacy of OO and FO in mitigating endothelial dysfunction and disruption of hemostasis caused by exposure to particulate matter (PM).Methods and ResultsForty-two participants (58 ± 1 years of age) received either 3 g/day of OO or FO, or no supplements (naive) for 4 weeks prior to undergoing 2-hr exposures to filtered air and concentrated ambient particulate matter (CAP; mean, 253 ± 16 μg/m3). Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery preexposure, immediately postexposure, and 20 hr postexposure. Levels of endothelin-1 and markers of fibrinolysis and inflammation were also measured. The FMD was significantly lower after CAP exposure in the naive (–19.4%; 95% CI: –36.4, –2.3 per 100 μg/m3 CAP relative to baseline; p = 0.03) and FO groups (–13.7%; 95% CI: –24.5, –2.9; p = 0.01), but not in the OO group (–7.6%; 95% CI: –21.5, 6.3; p = 0.27). Tissue plasminogen activator levels were significantly increased immediately after (11.6%; 95% CI: 0.8, 22.2; p = 0.04) and 20 hr after CAP exposure in the OO group. Endothelin-1 levels were significantly increased 20 hr after CAP exposure in the naive group only (17.1%; 95% CI: 2.2, 32.0; p = 0.03).ConclusionsShort-term exposure to CAP induced vascular endothelial dysfunction. OO supplementation attenuated CAP-induced reduction of FMD and changes in blood markers associated with vasoconstriction and fibrinolysis, suggesting that OO supplementation may be an efficacious intervention to protect against vascular effects of exposure to PM.CitationTong H, Rappold AG, Caughey M, Hinderliter AL, Bassett M, Montilla T, Case MW, Berntsen J, Bromberg PA, Cascio WE, Diaz-Sanchez D, Devlin RB, Samet JM. 2015. Dietary supplementation with olive oil or fish oil and vascular effects of concentrated ambient particulate matter exposure in human volunteers. Environ Health Perspect 123:1173–1179; http://dx.doi.org/10.1289/ehp.140898