E-cigarettes: A framework for comparative history and policy.

BACKGROUND: England, Australia and the United States have approached the regulation of e-cigarettes in very different ways, yet all three countries have appealed to the concept of evidence as underpinning policy responses. We compared these policy responses using a combination of the methodologies of historians and policy scientists in order to elucidate the factors that had influenced policy in each country. ARGUMENT/ANALYSIS: Each country's evidence and values intersected in different ways, producing very different responses within specific national contexts and histories. Our analysis accordingly emphasized the historical precursors of the policy issues raised by e-cigarettes and placed the policy debate within the context of regulatory bodies and the networks of researchers and advocates who influenced policy. Issues also of importance were the nature of the state; political context; the pre-history of nicotine for smoking cessation; the role of activism and its links with government; the influence of harm reduction ideas from drugs and HIV; and finally, whom policy was perceived to benefit. In the United Kingdom, based on this pre-history of the smoking issue, it was the existing smoker, while in the United States and Australia, protecting children and adolescents has played a central role. CONCLUSIONS: Structural and historical factors appear to underpin differences in e-cigarette policy development in England, Australia and the United States.

Education for public health 2030: transformation to meet health needs in a changing world.

Education for public health is at a critical inflection point, and either transforms for success or fails to remain relevant. In 2020, the Association for Schools and Programs of Public Health launched an initiative, Framing the Future 2030: Education for Public Health (FTF 2030) to develop a resilient educational system for public health that promotes scientific inquiry, connects research, education, and practice, eliminates inequities, incorporates anti-racism principles, creates and sustains diverse and inclusive teaching and learning communities, and optimizes systems and resources to prepare graduates who are clearly recognizable for their population health perspectives, knowledge, skills, attitudes, and practices. Three expert panels: (1) Inclusive excellence through an anti-racism lens; (2) Transformative approaches to teaching and learning; and (3) Expanding the reach, visibility, and impact of the field of academic public health are engaged in ongoing deliberations to generate recommendations to implement the necessary change. The article describes the panels' work completed thus far, a "Creating an Inclusive Workspace" guide, and work planned, including questions for self-evaluation, deliberation, and reflection toward actions that support academe in developing a resilient education system for public health, whether beginning or advancing through a process of change. The FTF 2030 steering committee asserts its strong commitment to structural and substantial change that strengthens academic public health as an essential component of a complex socio-political system. Lastly, all are called to join the effort as collaboration is essential to co-develop an educational system for public health that ensures health equity for all people, everywhere.

DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition.

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation. SIGNIFICANCE: We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587.

Identifying cellular signalling molecules in developmental disorders of the brain: Evidence from focal cortical dysplasia and tuberous sclerosis.

AIMS: We understand little of the pathogenesis of developmental cortical lesions, because we understand little of the diversity of the cell types that contribute to the diseases or how those cells interact. We tested the hypothesis that cellular diversity and cell-cell interactions play an important role in these disorders by investigating the signalling molecules in the commonest cortical malformations that lead to childhood epilepsy, focal cortical dysplasia (FCD) and tuberous sclerosis (TS). METHODS: Transcriptional profiling clustered cases into molecularly distinct groups. Using gene expression data, we identified the secretory signalling molecules in FCD/TS and characterised the cell types expressing these molecules. We developed a functional model using organotypic cultures. RESULTS: We identified 113 up-regulated secretory molecules in FCDIIB/TS. The top 12 differentially expressed genes (DEGs) were validated by immunohistochemistry. This highlighted two molecules, Chitinase 3-like protein 1 (CHI3L1) and C-C motif chemokine ligand 2 (CCL2) (MCP1) that were expressed in a unique population of small cells in close proximity to balloon cells (BC). We then characterised these cells and developed a functional model in organotypic slice cultures. We found that the number of CHI3L1 and CCL2 expressing cells decreased following inhibition of mTOR, the main aberrant signalling pathway in TS and FCD. CONCLUSIONS: Our findings highlight previously uncharacterised small cell populations in FCD and TS which express specific signalling molecules. These findings indicate a new level of diversity and cellular interactions in cortical malformations and provide a generalisable approach to understanding cell-cell interactions and cellular heterogeneity in developmental neuropathology.

A case series of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

In this study, we report three paediatric cases of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity.

Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas (n = 2325), malignant rhabdoid tumors (n = 229) and pediatric high-grade gliomas (n = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy.

Vexing, Veiled, and Inequitable: Social Distancing and the "Rights" Divide in the Age of COVID-19.

Although unprecedented in scope and beyond all our life experiences, sweeping social distancing measures are not without historical precedent. Historically, racism, stigma, and discrimination resulted in grossly inequitable application of disease containment measures. But history also provides examples in which broad measures enjoyed remarkable public support. When it comes to COVID-19, blame and division continue to shape containment responses. But the COVID-19 pandemic also resonates with moments in which there was broad social support for containment precisely because lockdowns or stay at home orders are, on the surface, remarkably equitable. Yet even in a context in which a majority of Americans support social distancing, small but coordinated conservative groups are challenging social distancing as a matter of individual rights. In sharp contrast, vulnerable populations, who bear the heaviest burden of disease, have claimed a right to social distancing as a matter of protection.

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890.

Recommendations for Cardiovascular Health and Disease Surveillance for 2030 and Beyond: A Policy Statement From the American Heart Association.

The release of the American Heart Association's 2030 Impact Goal and associated metrics for success underscores the importance of cardiovascular health and cardiovascular disease surveillance systems for the acquisition of information sufficient to support implementation and evaluation. The aim of this policy statement is to review and comment on existing recommendations for and current approaches to cardiovascular surveillance, identify gaps, and formulate policy implications and pragmatic recommendations for transforming surveillance of cardiovascular disease and cardiovascular health in the United States. The development of community platforms coupled with widespread use of digital technologies, electronic health records, and mobile health has created new opportunities that could greatly modernize surveillance if coordinated in a pragmatic matter. However, technology and public health and scientific mandates must be merged into action. We describe the action and components necessary to create the cardiovascular health and cardiovascular disease surveillance system of the future, steps in development, and challenges that federal, state, and local governments will need to address. Development of robust policies and commitment to collaboration among professional organizations, community partners, and policy makers are critical to ultimately reduce the burden of cardiovascular disease and improve cardiovascular health and to evaluate whether national health goals are achieved.

DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study.

BACKGROUND: Marked variation exists in the use of genomic data in tumour diagnosis, and optimal integration with conventional diagnostic technology remains uncertain despite several studies reporting improved diagnostic accuracy, selection for targeted treatments, and stratification for trials. Our aim was to assess the added value of molecular profiling in routine clinical practice and the impact on conventional and experimental treatments. METHODS: This population-based study assessed the diagnostic and clinical use of DNA methylation-based profiling in childhood CNS tumours using two large national cohorts in the UK. In the diagnostic cohort-which included routinely diagnosed CNS tumours between Sept 1, 2016, and Sept 1, 2018-we assessed how the methylation profile altered or refined diagnosis in routine clinical practice and estimated how this would affect standard patient management. For the archival cohort of diagnostically difficult cases, we established how many cases could be solved using modern standard pathology, how many could only be solved using the methylation profile, and how many remained unsolvable. FINDINGS: Of 484 patients younger than 20 years with CNS tumours, 306 had DNA methylation arrays requested by the neuropathologist and were included in the diagnostic cohort. Molecular profiling added a unique contribution to clinical diagnosis in 107 (35%; 95% CI 30-40) of 306 cases in routine diagnostic practice-providing additional molecular subtyping data in 99 cases, amended the final diagnosis in five cases, and making potentially significant predictions in three cases. We estimated that it could change conventional management in 11 (4%; 95% CI 2-6) of 306 patients. Among 195 historically difficult-to-diagnose tumours in the archival cohort, 99 (51%) could be diagnosed using standard methods, with the addition of methylation profiling solving a further 34 (17%) cases. The remaining 62 (32%) cases were unresolved despite specialist pathology and methylation profiling. INTERPRETATION: Together, these data provide estimates of the impact that could be expected from routine implementation of genomic profiling into clinical practice, and indicate limitations where additional techniques will be required. We conclude that DNA methylation arrays are a useful diagnostic adjunct for childhood CNS tumours. FUNDING: The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research.

Objective monitoring of mosquito bednet usage and the ethical challenge of privacy revelations about study bystanders: Ethical analysis.

Clinical trials and public health surveillance of bednet use for malaria prevention involve the ongoing collection of sensitive data from private settings. This article discusses risks to bystanders, who have not consented to participating in surveillance or research, but whose behavior may nevertheless be recorded. In the case of clinical trials, community consultation and consent processes are one well-accepted way to address potential risk to bystanders. I argue that the intrusive monitoring required by some bednet trials may render this type of consent insufficient. In these cases, either bystanders should be enrolled as participants and give consent or less intrusive monitoring methods should be used. Validated monitoring methods should also have relevance for practice beyond use in a clinical trial. Considering the global impact of malaria, applying these methods to public health surveillance would be a practical use. Existing justifications for surveillance without consent, which sometimes result in coercive public health measures, could apply to the case of bednets. Particularly in cases where there is the potential for harm to others, individuals who were not the original subjects of disease reporting are often caught in the surveillance net. Although an argument can be made that malaria meets this bar, considerations of feasibility, sustainability, and trust make intrusive surveillance unsustainable in the case of a daily, lifelong behavior such as bednet use.

The E-Cigarette Debate: What Counts as Evidence?

Two major public health evaluations of e-cigarettes-one from the National Academies of Science, Engineering, and Medicine (NASEM), the other from Public Health England (PHE)-were issued back to back in the winter of 2018. While some have read these analyses as broadly consistent, providing support for the view that e-cigarettes could play a role in smoking harm reduction, in every major respect, they come to very different conclusions about what the evidence suggests in terms of public health policy. How is that possible? The explanation rests in what the 2 reports see as the central challenge posed by e-cigarettes, which helped to determine what counted as evidence. For NASEM, the core question was how to protect nonsmokers from the potential risks of exposure to nicotine and other contaminants or from the risk of smoking combustible cigarettes through renormalization. A precautionary standard was imperative, making evidence that could speak most conclusively to the question of causality paramount. For PHE, the priority was how to reduce the burdens now borne by current smokers, burdens reflected in measurable patterns of morbidity and mortality. With a focus on immediate harms, PHE turned to evidence that was "relevant and meaningful." Thus, competing priorities determined what counted as evidence when it came to the impact of e-cigarettes on current smokers, nonsmoking bystanders, and children and adolescents. A new clinical trial demonstrating the efficacy of e-cigarettes as a cessation tool makes understanding how values and framing shape core questions and conclusive evidence imperative.

The Two Faces of Fear: A History of Hard-Hitting Public Health Campaigns Against Tobacco and AIDS.

Fear is now commonly used in public health campaigns, yet for years ethical and efficacy-centered concerns provided a challenge to using fear in such efforts. From the 1950s through the 1970s, the field of public health believed that using fear to influence individual behavior would virtually always backfire. Yet faced with the limited effectiveness of informational approaches to cessation, antitobacco campaigns featured fear in the 1960s. These provoked little protest outside the tobacco industry. At the outset of the AIDS epidemic, fear was also employed. However, activists denounced these messages as stigmatizing, halting use of fear for HIV/AIDS until the 21st century. Opposition began to fracture with growing concerns about complacency and the risks of HIV transmission, particularly among gay men. With AIDS, fear overcame opposition only when it was framed as fair warning with the potential to correct misperceptions.