COVID-19 pediatric vaccine authorization, FDA authority, and individual misperception of risk.

Vaccines are one component to the public health strategies to alleviate the COVID-19 pandemic. Hesitancy regarding COVID-19 vaccines in the United States has been problematic, which is not surprising given increasing overall vaccine hesitancy in recent decades. Most vaccines are administered during childhood years. Consequently, understanding hesitancy toward administration of vaccines in this age group may provide insight into possible interventions to reduce vaccine hesitancy. The present study analyzed a subset of over 130,000 public comments posted in response to a notice of meeting of the vaccine advisory group to the Food and Drug Administration. The meeting addressed whether to recommend Emergency Use Authorization ('EUA') of the COVID-19 vaccine for children ages 5-11. The results of the study demonstrate that most comments opposed EUA and these comments were associated with statements that indicated misperceptions of risk. Findings provide interesting insights regarding the role of public comments generally but also suggest that the public participation process in notice and comment can be modified to serve as an intervention to align individual perceptions of risk more closely with evidence-based assessment of risk. In addition, the findings provide opportunities to consider strategies for public health messaging.

Evaluation of Risk Perception of Smoking after the Implementation of California's Tobacco 21 Law.

Decreasing smoking initiation remains a public health priority. In 2016, California, in the United States, enacted the Tobacco 21 law, which raised the minimum age for the purchase of tobacco products from age 18 to age 21. This paper evaluates whether the enactment and implementation of the Tobacco 21 law changed how young adults perceive the risk(s) of smoking. Data were drawn from a cohort of emerging adults (n = 575) in California who were non-daily smokers at enrollment and followed quarterly for 3 years. Data were collected during 2015-2019. Piecewise multilevel regression models were used to test for changes in smoking status and perceived risks of cigarettes after Tobacco 21 enforcement began. Findings indicated that the prevalence of current smoking and perceived risks of smoking both declined following Tobacco 21 implementation (ps < 0.001). Post-hoc analyses suggested that post-implementation changes in perceived risk occurred primarily among ongoing smokers. Findings suggest that Tobacco 21 and associated public health measures have been effective, but additional research is needed to disentangle the effects of specific components. Understanding the impact and efficacy of tobacco laws provides great social value to research and implement policies that create intervention(s) on reducing tobacco use initiation.

COVID-19 Vaccine Hesitancy and (Mis)perception of Risk.

This Article tackles the critical problem of COVID-19 vaccine hesitancy and provides a normative framework for legal policies to address such hesitancy in the ongoing pandemic. The foundation of this Article rests in decision-making theories that allow policymakers to understand individual misperception of risk as compared to evidence-based assessment of risk. Vaccine-hesitant individuals assign a high risk to the COVID-19 vaccine and a low risk to the disease-a perception that is disconnected from the science. The backbone of this Article is the timeline of the COVID-19 pandemic and the underlying science of the disease and vaccines. The timeline provides a factual background to demonstrate how vaccine hesitancy to the COVID-19 vaccine emerged. The instant pandemic also demonstrates changes in how individuals see themselves in society, receive information, and are persuaded by economic forces. This Article combines the individual's decision-making process with modern day variables to suggest interventions that can undo anti-vaccine damage. While the novelty of the normative framework provided herein is instructive for current COVID-19 vaccine hesitancy issues, this framework can be applied to other areas in which individual's perceptions of risk are disconnected from evidence-based assessment of risk.

Biotechnology and Consumer Decision-Making.

Society is facing major challenges in climate change, health care and overall quality of life. Scientific advances to address these areas continue to grow, with overwhelming evidence that the application of highly tested forms of biotechnology is safe and effective. Despite scientific consensus in these areas, consumers appear reluctant to support their use. Research that helps to understand consumer decision-making and the public's resistance to biotechnologies such as vaccines, fluoridated water programs and genetically engineered food, will provide great social value. This article is forward-thinking in that it suggests that important research in behavioral decision-making, specifically affect and ambiguity, can be used to help consumers make informed choices about major applications of biotechnology. This article highlights some of the most controversial examples: vaccinations, genetically engineered food, rbST treated dairy cows, fluoridated water, and embryonic stem cell research. In many of these areas, consumers perceive the risks as high, but the experts calculate the risks as low. Four major thematic approaches are proposed to create a roadmap for policymakers to consider for policy design and implementation in controversial areas of biotechnology. This article articulates future directions for studies that implement decision-making research to allow consumers to appropriately assign risk to their options and make informed decisions.

Food Labeling and Consumer Associations with Health, Safety, and Environment.

The food supply is complicated and consumers are increasingly calling for labeling on food to be more informative. In particular, consumers are asking for the labeling of food derived from genetically modified organisms (GMO) based on health, safety, and environmental concerns. At issue is whether the labels that are sought would accurately provide the information desired. The present study examined consumer (n = 181) perceptions of health, safety and the environment for foods labeled organic, natural, fat free or low fat, GMO, or non-GMO. Findings indicated that respondents consistently believed that foods labeled GMO are less healthy, safe and environmentally-friendly compared to all other labels (ps < .05). These results suggest that labels mean something to consumers, but that a disconnect may exist between the meaning associated with the label and the scientific consensus for GMO food. These findings may provide insight for the development of labels that provide information that consumers seek.

Dietary Supplements are Not all Safe and Not all Food: How the Low Cost of Dietary Supplements Preys on the Consumer.

Dietary supplements are regulated as food, even though the safety and efficacy of some supplements are unknown. These products are often promoted as 'natural.' This leads many consumers to fail to question the supplements' safety, and some consumers even equate 'natural' with safe. But, 'natural' does not mean safe. For example, many wild berries and mushrooms are dangerous although they are natural. Another example is tobacco--a key ingredient in cigarettes: it is natural, but overwhelming studies have established the harm of cigarette smoke. The Food and Drug Administration (FDA) requires safety and efficacy testing prior to market entry for drugs. In contrast, the FDA only has limited ability to regulate the entry of new dietary supplements into the marketplace because supplements are treated as food. Two main arguments support the current regulatory structure of dietary supplements: (1) cost and (2) access. But lower cost and increased access to dietary supplements do not necessary have any relationship to safety and efficacy. Manufacturers' marketing techniques tout the health benefits of their supplements. Meanwhile, consumers are ingesting supplements without scientific studies indicating whether or not they are harmful. The FDA Food Safety and Modernization Act, signed into law on January 4, 2011, did not address the safety concerns regarding dietary supplements. This article discusses the regulatory deficiencies concerning dietary supplements and proposes novel solutions to address this specific sector of the food supply. This article advocates for the use of scientific data to support a multi-tiered classification system to ensure that dietary supplements on the market are safe.

Financial conflicts of interest in science.

This Article proposes a new direction for addressing financial conflicts of interest, which plague biomedical research and threaten scientific integrity. This Article descriptively states the controversy surrounding financial conflicts of interest by explaining how these conflicts arise and the damage that can be created as a result. By describing the scientific process, the Article explains that changes to the academic environment may allow the public-private interaction to proceed, without creating the problems associated with financial conflicts of interest. Financial conflicts of interest are created when the profit-seeking motive of a private funding source unduly influences an academic scientist's primary responsibilities. The problem with financial conflicts of interest has grown since the passage of the Bayh-Dole Act in 1980. The cornerstone of current policies to address financial conflicts of interest is disclosure, which is inadequate and unsatisfying. The analysis herein changes the trajectory of current approaches in this area by proposing that an analysis of the underlying environment and behavior leading to conflicts of interest must be considered. This Article proposes the use of behavioral economics to craft a policy that effectively addresses conflicts of interest. To this end, this Article applies research from the field of psychology to understand both the environment of academic scientists as well as to begin to understand how academic scientists make decisions. Drawing on psychology literature, this article proposes that academic scientists may experience cognitive dissonance when faced with a situation in which a conflict of interest may arise. This helps to understand why an academic scientist may make a decision that creates a conflict of interest. In addition, this Article utilizes the results of an empirical study conducted by myself and a colleague. In this study, we asked faculty at five medical schools to respond to an anonymous survey containing hypothetical situations in which a conflict may arise. The combination of the psychology literature and our empirical study can provide support to the creation of new policies. Policy proposals include implementation of default rules, education, and changes to academic requirements. Furthermore, this Article considers ways to incentivize medical centers to implement effective policies as well as changes to intellectual property law.

Evaluation of academic scientists' responses to situations that pose a conflict of interest.

The industry-academy relationship has many benefits, but it also has potential drawbacks, including potential conflicts of interest (e.g., when the profit motives of a private company unduly influence academic responsibilities). To date, policies intended to regulate or manage financial conflicts of interest appear to be unsatisfying and inadequate. The present study examined predictors of the responses of academic scientists and clinicians to hypothetical situations in which financial and other conflicts of interest may arise. Academic scientists and clinicians at five medical schools completed an anonymous survey that included vignettes that posed a potential conflict of interest. Participants indicated the likelihood that they would engage in specific actions to avoid conflicts of interest. Findings indicated that junior faculty and those whose departments received more federal grant money were more likely to respond in ways that could create conflicts of interest (ps < .05). These results suggest that various sub-groups of faculty may require different approaches to appropriately avoid or manage financial conflicts of interest. These findings may contribute to the development of new policies that deal more effectively with conflicts of interest.

The states "race" with the federal government for stem cell research.

This article presents an innovative study of the effect of individual states and private institutes in pushing forward stem cell research despite a federal ban on creating new stem cell lines. The author analyzes the impact of state legislation, proposing that states are reacting to federal policy by serving as laboratories for what is traditionally federally funded biomedical research.

Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth.

p53-dependent apoptosis is a major determinant of its tumor suppressor activity and can be triggered by hypoxia. No p53 target is known to be induced by p53 or to mediate p53-dependent apoptosis during hypoxia. We report that p53 can directly upregulate expression of Bnip3L, a cell death inducer. During hypoxia, Bnip3L is highly induced in wild-type p53-expressing cells, in part due to increased recruitment of p53 and CBP to Bnip3L. Apoptosis is reduced in hypoxia-exposed cells with functional p53 following Bnip3L knockdown. In vivo, Bnip3L knockdown promotes tumorigenicity of wild-type versus mutant p53-expressing tumors. Thus, Bnip3L, capable of attenuating tumorigenicity, mediates p53-dependent apoptosis under hypoxia, which provides a novel understanding of p53 in tumor suppression.

Microarray expression profiling of p53-dependent transcriptional changes in an immortalized mouse embryo fibroblast cell line.

The ability of p53 to transcriptionally regulate genes involved with cell cycle progression and apoptosis is critical to its role as a tumor suppressor. Although numerous p53 regulated genes have been identified over the last several years, ablation of any one of these genes cannot account for the full p53-mediated cellular response. Therefore, we performed microarray analysis using two related p53 temperature sensitive cell lines, Val5 and Vm10, to identify novel p53 regulated genes. The Val5 cells undergo p53-mediated cell cycle arrest and the Vm10 cells undergo p53-mediated apoptosis when p53 is in the wild-type conformation. By using these two cell lines, we can compare which genes are regulated by p53 in two different conditions as well as analyze which genes are common to both cell lines. Using the information obtained in the microarray analysis, we confirmed whether a small sub-set of the genes was regulated by p53 using northern blot analysis. By identifying and confirming the regulation of specific genes by p53, we can further characterize biologically why p53 transcriptionally regulates these genes.

p53-induced gene expression analysis.

Researchers in the p53 field have successfully used many high-throughput screening technologies to analyze and characterize p53-induced gene expression. This chapter will focus on one such technology, the Affymetrix GeneChip. DNA-Chip technology has grown rapidly over the last several years. The ability to hybridize RNA from a sample to thousands to tens of thousands of known and unknown cDNAs spotted on a microarray chip has led to the explosion of information ranging from macro-global expression pattern changes to micro-gene-specific expression changes. The relative ease of making a nonradioactive probe from either total RNA or mRNA to be hybridized to a GeneChip makes microarray technology highly attractive.

Identification and characterization of the cytoplasmic protein TRAF4 as a p53-regulated proapoptotic gene.

The role of p53 in tumor suppression partly relies on its ability to transcriptionally regulate target genes involved in the initiation of cell cycle arrest or the activation of programmed cell death. In recent years many genes have been identified as p53-regulated genes; however, no single target gene has been shown to be required for the full apoptotic effect. We have identified TRAF4 as a p53-regulated gene in a microarray screen using a Murine 11K Affymetrix GeneChip hybridized with cRNA from the p53 temperature-sensitive cell line, Vm10. TRAF4 is a member the TRAF family of adaptor proteins that mediate cellular signaling by binding to various members of the tumor necrosis family receptor superfamily and interleukin-1/Toll-like receptor super-family. In contrast to its other family members, TRAF4 has not been shown to bind to a member of the tumor necrosis factor receptor superfamily in vivo, nor has it been shown to regulate signaling pathways common to its other family members. Therefore the role of TRAF4 in a signaling pathway has not yet been established and requires further study. TRAF4 is specifically regulated by p53 in response to temperature sensitive p53, overexpression of p53 by use of an adenovirus, and stabilization of p53 in response to DNA damage. The murine TRAF4 promoter contains a functional p53 DNA-binding site approximately 1 kilobase upstream of the initiating methionine. TRAF4 localizes to the cytoplasm and appears to remain in the cytoplasm following DNA damage. Interestingly, the overexpression of TRAF4 induces apoptosis and suppresses colony formation. These data suggest a correlation that the orphan adaptor protein TRAF4 may play a role in p53-mediated proapoptotic signaling in the response to cellular stress.

The cyclin-dependent kinase inhibitor butyrolactone is a potent inhibitor of p21 (WAF1/CIP1 expression).

Butyrolactone I (BL) is a competitive inhibitor of ATP for binding and activation of cyclin-dependent kinases and is a potent inhibitor of cell cycle progression. Treatment of H460 human lung and SW480 human colon cancer cells with doses of BL that exceed the Ki for CDK inhibition but which are much lower than doses required to inhibit MAPK, PKA, PKC, or EGFR lead to a rapid significant reduction of endogenous p21 protein expression. BL-dependent inhibition of p21 expression appears to be p53-independent. BL-dependent p21 degradation was blocked by lactacystin, consistent with the hypothesis that there is accelerated p21 proteasomal degradation in the presence of BL. BL also inhibited the p53-dependent increase of p21 protein expression in cells exposed to the DNA damag-ing agent etoposide, and favored a greater G2/M arrest as compared to the non-BL exposed cells. BL accelerated the degradation of exogenously expressed p21 that was not observed with a C-terminal truncated form of p21. Degradation of exogenous p21 led to a shift to G2 accumulation in the cells exposed to BL. We conclude that BL has effects on the cell cycle beyond its role as a CDK inhibitor and can be used as a novel tool to study the mechanism of p21 degradation and the consequences towards p21- dependent checkpoints.

BID regulation by p53 contributes to chemosensitivity.

The role of the p53 protein (encoded by TP53) in tumour suppression relies partly on the ability of p53 to regulate the transcription of genes that are important in cell-cycle arrest and in apoptosis. But the apoptotic pathway mediated by p53 is not fully understood. Here we show that BID, a member of the pro-apoptotic Bcl-2 family of proteins, is regulated by p53. BID mRNA is increased in a p53-dependent manner in vitro and in vivo, with strong expression in the splenic red pulp and colonic epithelium of gamma-irradiated mice. Both the human and the mouse BID genomic loci contain p53-binding DNA response elements that bind p53 and mediate p53-dependent transactivation of a reporter gene. In addition, BID-null mouse embryonic fibroblasts are more resistant than are wild-type fibroblasts to the DNA damaging agent adriamycin and the nucleotide analogue 5-fluorouracil, both of which stabilize endogenous p53. Our results indicate that BID is a p53-responsive 'chemosensitivity gene' that may enhance the cell death response to chemotherapy.