Co-production and Managing Uncertainty in Health Research Regulation: A Delphi Study.

European and international regulation of human health research is typified by a morass of interconnecting laws, diverse and divergent ethical frameworks, and national and transnational standards. There is also a tendency for legislators to regulate in silos-that is, in discrete fields of scientific activity without due regard to the need to make new knowledge as generalisable as possible. There are myriad challenges for the stakeholders-researchers and regulators alike-who attempt to navigate these landscapes. This Delphi study was undertaken in order to provide the first interdisciplinary and crosscutting analysis of health research regulation, as it is experienced by such stakeholders in the UK context. As well as reinforcing existing understandings of the regulatory environment, Delphi participants called for greater collaboration, and even co-production, of processes involved in health research regulation. On the basis of this research, we offer insights about how health research regulation can become a matter with which a wider range of stakeholders-including researchers, regulators, publics and research sponsors-can engage. The evidence supports the normative claim that health research regulation should continue to move away from strict, prescriptive rules-based approaches, and towards flexible principle-based regimes that allow researchers, regulators and publics to co-produce regulatory systems serving core principles. By unpacking thorny concepts and practices at the heart of health research regulation-including the public interest and public engagement-our results have the potential to situate and breathe life into them. The results also demonstrate that while proportionality is well-recognised as a crucial element of flexible regulatory systems, more must be done to operationalise this as an ethical assessment of the values and risks at stake at multiple junctures in the research trajectory. This is required if we are to move beyond proportionality as a mere risk-management tool. Compliance culture no longer accurately reflects the needs and expectations of researchers or regulators, nor does it necessarily produce the best research. Embracing uncertainty-both as a human practice and a regulatory objective-may represent the brighter future for health research.

Caste- and pesticide-specific effects of neonicotinoid pesticide exposure on gene expression in bumblebees.

Social bees are important insect pollinators of wildflowers and agricultural crops, making their reported declines a global concern. A major factor implicated in these declines is the widespread use of neonicotinoid pesticides. Indeed, recent research has demonstrated that exposure to low doses of these neurotoxic pesticides impairs bee behaviours important for colony function and survival. However, our understanding of the molecular-genetic pathways that lead to such effects is limited, as is our knowledge of how effects may differ between colony members. To understand what genes and pathways are affected by exposure of bumblebee workers and queens to neonicotinoid pesticides, we implemented a transcriptome-wide gene expression study. We chronically exposed Bombus terrestriscolonies to either clothianidin or imidacloprid at field-realistic concentrations while controlling for factors including colony social environment and worker age. We reveal that genes involved in important biological processes including mitochondrial function are differentially expressed in response to neonicotinoid exposure. Additionally, clothianidin exposure had stronger effects on gene expression amplitude and alternative splicing than imidacloprid. Finally, exposure affected workers more strongly than queens. Our work demonstrates how RNA-Seq transcriptome profiling can provide detailed novel insight on the mechanisms mediating pesticide toxicity to a key insect pollinator.

Charting Regulatory Stewardship in Health Research: Making the Invisible Visible.

This section focuses on the ethical, legal, social, and policy questions arising from research involving human and animal subjects.

Defining an epidemic: the body mass index in British and US obesity research 1960-2000.

Between the 1970s and the mid-1990s the body mass index (BMI) became the standard means of assessing obesity both in populations and in individuals, replacing previously diverse and contested definitions of excess body weight. This article draws on theoretical approaches from the sociology of standards and science and technology studies to describe the development of this important new standard and the ways in which its adoption facilitated the development of obesity science, that is, knowledge about the causes, health effects and treatments of excess body weight. Using an analysis of policy and healthcare literatures, I argue that the adoption of the BMI, along with associated standard cut-off points defining overweight and obesity, was crucial in the framing of obesity as an epidemic. This is because, I suggest, these measures enabled, firstly, the creation of large data sets tracking population-level changes in average body weight, and, secondly, the construction of visual representations of these changes. The production of these two new techniques of representation made it possible for researchers in this field, and others such as policymakers, to argue credibly that obesity should be described as an epidemic.

Differing taxonomic responses of mosquito vectors to anthropogenic land-use change in Latin America and the Caribbean.

Anthropogenic land-use change, such as deforestation and urban development, can affect the emergence and re-emergence of mosquito-borne diseases, e.g., dengue and malaria, by creating more favourable vector habitats. There has been a limited assessment of how mosquito vectors respond to land-use changes, including differential species responses, and the dynamic nature of these responses. Improved understanding could help design effective disease control strategies. We compiled an extensive dataset of 10,244 Aedes and Anopheles mosquito abundance records across multiple land-use types at 632 sites in Latin America and the Caribbean. Using a Bayesian mixed effects modelling framework to account for between-study differences, we compared spatial differences in the abundance and species richness of mosquitoes across multiple land-use types, including agricultural and urban areas. Overall, we found that mosquito responses to anthropogenic land-use change were highly inconsistent, with pronounced responses observed at the genus- and species levels. There were strong declines in Aedes (-26%) and Anopheles (-35%) species richness in urban areas, however certain species such as Aedes aegypti, thrived in response to anthropogenic disturbance. When abundance records were coupled with remotely sensed forest loss data, we detected a strong positive response of dominant and secondary malaria vectors to recent deforestation. This highlights the importance of the temporal dynamics of land-use change in driving disease risk and the value of large synthetic datasets for understanding changing disease risk with environmental change.

Synergies between environmental degradation and climate variation on malaria re-emergence in southern Venezuela: a spatiotemporal modelling study.

BACKGROUND: Environmental degradation facilitates the emergence of vector-borne diseases, such as malaria, through changes in the ecological landscape that increase human-vector contacts and that expand vector habitats. However, the modifying effects of environmental degradation on climate-disease relationships have not been well explored. Here, we investigate the rapid re-emergence of malaria in a transmission hotspot in southern Venezuela and explore the synergistic effects of environmental degradation, specifically gold-mining activity, and climate variation. METHODS: In this spatiotemporal modelling study of the 46 parishes of the state of Bolívar, southeast Venezuela, we used data from the Venezuelan Ministry of Health including population data and monthly cases of Plasmodium falciparum malaria and Plasmodium vivax malaria between 1996 and 2016. We estimated mean precipitation and temperature using the ERA5-Land dataset and used monthly anomalies in sea-surface temperature as an indicator of El Niño events between 1996 and 2016. The location of suspected mining sites in Bolívar in 2009, 2017, and 2018 were sourced from the Amazon Geo-Referenced Socio-Environmental Information Network. We estimated measures of cumulative forest loss and urban development by km2 using annual land cover maps from the European Space Agency Climate Change Initiative between 1996 and 2016. We modelled monthly cases of P falciparum and P vivax malaria using a Bayesian hierarchical mixed model framework. We quantified the variation explained by mining activity before exploring the modifying effects of environmental degradation on climate-malaria relationships. FINDINGS: We observed a 27% reduction in the additional unexplained spatial variation in incidence of P falciparum malaria and a 23% reduction in P vivax malaria when mining was included in our models. The effect of temperature on malaria was greater in high mining areas than low mining areas, and the P falciparum malaria effect size at temperatures of 26·5°C (2·4 cases per 1000 people [95% CI 1·78-3·06]) was twice as high as the effect in low mining areas (1 case per 1000 people [0·68-1·49]). INTERPRETATION: We show that mining activity in southern Venezuela is associated with hotspots of malaria transmission. Increased temperatures exacerbated malaria transmission in mining areas, highlighting the need to consider how environmental degradation modulates climate effect on disease risk, which is especially important in areas subjected to rapidly rising temperatures and land-use change globally. Our findings have implications for the progress towards malaria elimination in the Latin American region. Our findings are also important for effectively targeting timely treatment programmes and vector-control activities in mining areas with high rates of malaria transmission. FUNDING: Biotechnology and Biological Sciences Research Council, Royal Society, US National Institutes of Health, and Global Challenges Research Fund. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Climate services for health: From global observations to local interventions.

Despite the wealth of available climate data available, there is no consensus on the most appropriate product choice for health impact modelling and how this influences downstream climate-health decisions. We discuss challenges related to product choice, highlighting the importance of considering data biases and co-development of climate services between different sectors.

Epidemiological, socio-demographic and clinical features of the early phase of the COVID-19 epidemic in Ecuador.

The SARS-CoV-2 virus has spread rapidly around the globe. Nevertheless, there is limited information describing the characteristics and outcomes of COVID-19 patients in Latin America. We conducted a cross-sectional analysis of 9,468 confirmed COVID-19 cases reported in Ecuador. We calculated overall incidence, mortality, case fatality rates, disability adjusted life years, attack and crude mortality rates, as well as relative risk and relative odds of death, adjusted for age, sex and presence of comorbidities. A total of 9,468 positive COVID-19 cases and 474 deaths were included in the analysis. Men accounted for 55.4% (n = 5, 247) of cases and women for 44.6% (n = 4, 221). We found the presence of comorbidities, being male and older than 65 years were important determinants of mortality. Coastal regions were most affected by COVID-19, with higher mortality rates than the highlands. Fatigue was reported in 53.2% of the patients, followed by headache (43%), dry cough (41.7%), ageusia (37.1%) and anosmia (36.1%). We present an analysis of the burden of COVID-19 in Ecuador. Our findings show that men are at higher risk of dying from COVID-19 than women, and risk increases with age and the presence of comorbidities. We also found that blue-collar workers and the unemployed are at greater risk of dying. These early observations offer clinical insights for the medical community to help improve patient care and for public health officials to strengthen Ecuador's response to the outbreak.

Beyond regulatory compression: confronting the liminal spaces of health research regulation.

Biomedicine and the life sciences continuously rearrange the relationship between culture and biology. In consequence, we increasingly look for a suitable regulatory response to reduce perceived uncertainty and instability. This article examines the full implications of this 'regulatory turn' by drawing on the anthropological concept of liminality. We offer the term 'regulatory compression' to characterise the effects of extant regulatory approaches on health research practices. With its focus on transformation and the 'in-between', liminality allows us to see how regulatory frameworks rely on a silo-based approach to classifying and regulating research objects such that they: (1) limit the flexibility necessary in clinical and laboratory research; (2) result in the emergence of unregulated spaces that lie between the bounded regulatory spheres; and (3) curtail modes of public participation in the health research enterprise. We suggest there is a need to develop the notion of 'processual regulation', a novel framework that requires a temporal-spatial examination of regulatory spaces and practices as these are experienced by all actors, including the relationship of actors with the objects of regulation.