Three Models of Community-Based Participatory Research

Community-based participatory research (CBPR) is a collaborative process between community-based organizations and academic investigators. It has the potential to make research more responsive to existing needs and to enhance a community’s ability to address important health issues. But CBPR is often unfamiliar territory to academic investigators and community organizations alike. We interviewed CBPR investigators at Penn and community leaders to ascertain best practices in CBPR and to compare academic and community perspectives. A number of models of community-academic partnerships emerged, each with its own advantages and disadvantages. The perspectives of the investigators sometimes matched those of the community leaders, but diverged in important ways

Adherence to Cancer Prevention Guidelines in 18 African Countries

Background Cancer rates in Africa are projected to double by 2030 due to aging and increased exposure to cancer risk factors, including modifiable risk factors. We assessed adherence to 5 modifiable cancer risk factors across 18 African countries. Methods Data on adults 18 years and older were obtained from the 2002–2004 World Health Survey. Adherence to current World Cancer Research Fund guidelines on smoking, alcohol, body weight, physical activity, and nutrition was assessed. Adherence scores ranged from 0 (no guideline met) to 5 (all guidelines met). Determinants of adherence were assessed using multivariable linear regression adjusted for individual and country level characteristics. Results Across all countries, adherence to the guidelines among adults was high for smoking (72%–99%) and alcohol (85%–100%), but low for body weight (1.8%–78%), physical activity (3.4%–84%) and nutrition (1.4%–61%). Overall adherence score ranged from 2.32 in Mali to 3.72 in Comoros. In multivariable models, residing in low versus high SES households was associated with reduced adherence by 0.24 and 0.21 points for men and women respectively after adjusting for age, gender, education, and marital status (p<0.001). Every % increase in GDP spent on health was associated with increased adherence by 0.03 in men and 0.09 in women (p<0.001). Conclusions The wide variation in adherence to cancer prevention guidelines observed across countries and between population sub-groups suggests the need for targeted public health efforts to improve behaviors related to body weight, physical activity and nutrition

Conducting Precision Medicine Research with African Americans

Importance Precision medicine is an approach to detecting, treating, and managing disease that is based on individual variation in genetic, environmental, and lifestyle factors. Precision medicine is expected to reduce health disparities, but this will be possible only if studies have adequate representation of racial minorities. Objective It is critical to anticipate the rates at which individuals from diverse populations are likely to participate in precision medicine studies as research initiatives are being developed. We evaluated the likelihood of participating in a clinical study for precision medicine. Design, Setting, Participants Observational study conducted between October 2010 and February 2011 in a national sample of African Americans. Main Outcome Measure Intentions to participate in a government sponsored study that involves providing a biospecimen and generates data that could be shared with other researchers to conduct future studies. Results One third of respondents would participate in a clinical study for precision medicine. Only gender had a significant independent association with participation intentions. Men had a 1.86 (95% CI = 1.11, 3.12, p = 0.02) increased likelihood of participating in a precision medicine study compared to women in the model that included overall barriers and facilitators. In the model with specific participation barriers, distrust was associated with a reduced likelihood of participating in the research described in the vignette (OR = 0.57, 95% CI = 0.34, 0.96, p = 0.04). Conclusion and Relevance African Americans may have low enrollment in PMI research. As PMI research is implemented, extensive efforts will be needed to ensure adequate representation. Additional research is needed to identify optimal ways of ethically describing precision medicine studies to ensure sufficient recruitment of racial minorities

Plant cell culture platforms for production of bioscavengers for biodefense

There is a critical need for flexible, rapid, cost effective biomanufacturing platforms for medical countermeasures. Our team has developed plant cell culture-based manufacturing platforms for production of recombinant protein bioscavengers against organophosphate (OP) nerve agents and anthrax toxins using both stable transgenic cell cultures for known chemical and biological threats, as well as transient production for rapid response to new and/or unanticipated threats. Plant cells offer several advantages over other hosts for production of medical countermeasures, particularly their ability to produce complex biologics and perform post-translational modification, inherent biosafety since they don\u27t harbor or propagate mammalian viruses thereby simplifying and/or eliminating viral clearance steps required for mammalian production systems. Plant cells are robust, have minimal nutrient requirements (grow in simple, chemically defined media containing sucrose, salts and plant hormones), and are relatively insensitive to changes in environmental conditions. These characteristics, robustness of upstream cultivation/use and reduced downstream purification requirements, make plant cells an ideal choice for field-deployable production of medical countermeasures. Here we present results for the production of functional recombinant butyrylcholinesterase (BChE), an OP nerve agent bioscavenger, in transgenic rice cell suspension cultures in different bioreactor configurations, and transient production of a bioscavenger against an anthrax toxin in N. benthamiana cell cultures. Techno-economic models for scaled-up versions of these plant cell culture production systems will also be presented

Semicontinuous Bioreactor Production of Recombinant Butyrylcholinesterase in Transgenic Rice Cell Suspension Cultures.

An active and tetrameric form of recombinant butyrylcholinesterase (BChE), a large and complex human enzyme, was produced via semicontinuous operation in a transgenic rice cell suspension culture. After transformation of rice callus and screening of transformants, the cultures were scaled up from culture flask to a lab scale bioreactor. The bioreactor was operated through two phases each of growth and expression. The cells were able to produce BChE during both expression phases, with a maximum yield of 1.6 mg BChE/L of culture during the second expression phase. Cells successfully regrew during a 5-day growth phase. A combination of activity assays and Western blot analysis indicated production of an active and fully assembled tetramer of BChE

The association of alcohol consumption with mammographic density in a multiethnic urban population

Background Alcohol consumption is associated with higher breast cancer risk. While studies suggest a modest association between alcohol intake and mammographic density, few studies have examined the association in racial/ethnic minority populations. Methods We assessed dense breast area and total breast area from digitized film mammograms in an urban cohort of African American (42%), African Caribbean (22%), white (22%), and Hispanic Caribbean (9%) women (n = 189, ages 40-61). We examined the association between alcohol intake and mammographic density (percent density and dense area). We used linear regression to examine mean differences in mammographic density across alcohol intake categories. We considered confounding by age, body mass index (BMI), hormone contraceptive use, family history of breast cancer, menopausal status, smoking status, nativity, race/ethnicity, age at first birth, and parity. Results Fifty percent currently consumed alcohol. Women who consumed >7 servings/week of alcohol, but not those consuming ≤7 servings/week, had higher percent density compared to nondrinkers after full adjustments (servings/week >7 β = 8.2, 95% Confidence Interval (CI) 1.8, 14.6; ≤7 β = -0.5, 95% CI -3.7, 2.8). There was a positive association between high alcohol intake and dense area after full adjustments (servings/week >7 β = 5.8, 95% CI -2.7, 14.2; ≤7 β = -0.1, 95% CI -4.4, 4.2). We did not observe race/ethnicity modification of the association between alcohol intake and percent density. In women with a BMI of 7 servings/week of alcohol had a 17% increase in percent density compared to nondrinkers (95% CI 5.4, 29.0) and there was no association in women with a BMI ≥ 25 kg/m2 (BMI ≥ 25-30 kg/m2 > 7 β = 5.1, 95% CI -8.5, 18.7 and BMI > 30 kg/m2 > 7 β = 0.5, 95% CI -6.5, 7.5) after adjusting for age and BMI (continuous). Conclusion In a racially/ethnically diverse cohort, women who consumed >7 servings/week of alcohol, especially those with a BMI < 25 kg/m2, had higher percent density. Keywords: Mammographic breast density; Alcohol consumption; Breast cance

Alcohol consumption and breast cancer-specific and all-cause mortality in women diagnosed with breast cancer at the New York site of the Breast Cancer Family Registry

Purpose Alcohol consumption is an established and important risk factor for breast cancer incidence in the general population. However, the relationship between alcohol and mortality among women with breast cancer is less clear. This study examines the effect of alcohol consumption on mortality in women affected with breast cancer at baseline from a high-risk family breast and ovarian cancer registry. Methods We studied 1116 women affected with breast cancer at baseline from the Metropolitan New York Registry. The examined reported alcohol consumption (total of beer, wine, liquor) was defined as the average number of drinks per week reported from age 12 to age at baseline. We assessed vital status of each participant using participant or family reported data and we used the National Death Index to supplement deaths reported through family updates. We used Cox proportional hazards models to estimate the association between alcohol intake and overall mortality (HRO), breast cancer-specific mortality (HRBC), and non-breast cancer mortality (HRNBC), adjusted for confounders. Results After a mean follow-up of 9.1 years, we observed 211 total deaths and 58 breast cancer deaths. Compared to non-drinkers, we found that both low and moderate to heavy levels of alcohol intake were not associated with greater overall mortality (≤3 drinks/week: HRO: 0.66, 95% CI: 0.38–1.14); > 3 drinks/week: HRO: 1.16, 95% CI: 0.85–1.58), breast cancer–specific mortality (≤ 3 drinks/week: HRBC:0.62, 95% CI: 0.19–2.03; >3 drinks/week: HR BC: 0.96, 95% CI: 0.49–1.89), or non-breast cancer-specific mortality (≤3 drinks/week: HR NBC: 0.73, 95% CI: 0.32–1.6; >3 drinks/week: HRNBC: 1.18, 95% CI: 0.75–1.86). Conclusions Alcohol intake reported from age 12 to age at baseline was not associated with overall or breast cancer-specific mortality in this cohort of affected women with a family history of breast cancer

A novel plant cell culture platform for semicontinous production of recombinant proteins: Butyrylcholinesterase as a case study

In this paper we describe a novel biomanufacturing production platform that utilizes transgenic rice cell suspension cultures for efficient semicontinuous cell culture (SCC) production of recombinant proteins. The production platform utilizes a metabolically regulated promoter, a secretion signal peptide that enables secretion out of the cell for ease of recovery/purification, coupled with an efficient semicontinuous operational strategy that allows independent optimization of growth and production phases. In addition, long term operation (up several months1) is possible by maintaining viable biomass within the bioreactor, thereby reducing the need for long seed trains, as well as minimizing turn-around time, CIP and SIP operations, chemicals and energy. This platform offers a number of advantages over traditional methods for production of recombinant therapeutic proteins that use E. coli, yeast or mammalian cell cultures, while still retaining the ability to meet cGMP regulatory requirements under well-controlled, reproducible production conditions. Traditional methods for production of biologics use genetically modified E. coli, yeast, insect or mammalian cell cultures in bioreactor systems. For applications where a human therapeutic protein (monoclonal antibodies, vaccines, bioscavengers, replacement biologics) produced under strict cGMP conditions are required, plant cell cultures offer a number of advantages over currently used bioreactor-based systems, including low risk of contamination by mammalian viruses, blood-borne pathogens, prions or bacterial endotoxins or mycoplasma, the ability to perform complex glycosylation, ease of culturing compared with other higher eukaryotic hosts, the ability to target the product to the extracellular medium, and the ability to grow in simple, low cost, chemically defined and animal component-free medium. In this paper we describe the specific characteristics of the rice cell suspension culture that make them particularly useful for continuous operation and superior to other hosts including their slow death rates, growth in small aggregates, limited secretome, and robustness under culture conditions. In addition, the regulatory pathway for plant-based recombinant biologics for human therapeutic use has now been established. ElelysoTM, produced in carrot cell suspension in batch culture by Protalix Biotherapeutics and Pfizer, Inc. for treatment of Gaucher disease was approved by the FDA in May 20122, 3. The transgenic rice cell culture system is operated in a cyclical, semicontinuous operation as shown in Figure 1. Note that gravity sedimentation within the bioreactor can be used to separate the plant cell aggregates from the liquid phase in Steps 3 and 6, and that the product collected in Step 6 can be purified either using a batch downstream strategy or collected to feed a continuous downstream process. Results will be presented for semicontinuous production of butyrylcholinesterase, a bioscavenger for organophosphorus nerve agents such as sarin, using the metabolically regulated transgenic rice cell culture in 5 L bioreactors

Critical Review on the Public Health Impact of Norovirus Contamination in Shellfish and the Environment:A UK Perspective

We review the risk of norovirus (NoV) infection to the human population from consumption of contaminated shellfish. From a UK perspective, risk is apportioned for different vectors of NoV infection within the population. NoV spreads mainly by person-to-person contact or via unsanitary food handling. NoV also enters the coastal zone via wastewater discharges resulting in contamination of shellfish waters. Typically, NoV persists in the marine environment for several days, with its presence strongly linked to human population density, wastewater discharge rate, and efficacy of wastewater treatment. Shellfish bioaccumulate NoV and current post-harvest depuration is inefficient in its removal. While NoV can be inactivated by cooking (e.g. mussels), consumption of contaminated raw shellfish (e.g. oysters) represents a risk to human health. Consumption of contaminated food accounts for 3–11% of NoV cases in the UK (~74,000 cases/year), of which 16% are attributable to oyster consumption (11,800 cases/year). However, environmental and human factors influencing NoV infectivity remain poorly understood. Lack of standard methods for accurate quantification of infective and non-infective (damaged) NoV particles represent a major barrier, hampering identification of an appropriate lower NoV contamination limit for shellfish. Future management strategies may include shellfish quality assessment (at point of harvest or at point of supply) or harvesting controls. However, poor understanding of NoV inactivation in shellfish and the environment currently limits accurate apportionment and risk assessment for NoV and hence the identification of appropriate shellfish or environmental quality standards