Characterising the nicotine metabolite ratio and its association with treatment choice: A cross sectional analysis of Stop Smoking Services in England

Pharmacotherapy provision based on Nicotine Metabolite Ratio (NMR) status (slow/normal metabolism) may improve smoking cessation rates. However, it is unclear whether NMR status is consistent across patient characteristics and current treatment choice. Data come from 1,826 participants attending Stop Smoking Services (SSS) across England in 2012/13. Sociodemographic, mental/physical health, smoking and treatment characteristics (nicotine replacement therapy vs. other pharmacotherapy; group vs. one-to-one behavioural support) were assessed. Salivary nicotine metabolites were measured and NMR (3-hydroxycotinine/cotinine) computed, characterising smokers as slow (NMR < 0.31) or normal (NMR ≥ 0.31) metabolisers. Normal metabolisers were older than slow metabolisers (Odds Ratio (OR) = 1.49, 95% Confidence Interval (CI) = 1.32-1.69) but no other characteristics were associated with NMR status. Overall, predictors accounted for only 7.3% of NMR variance. In adjusted analysis, pharmacotherapy type was not associated with NMR status, but normal metabolisers were less likely to use group support (OR = 0.67, 95% CI = 0.51-0.89). NMR status does not vary substantially across sociodemographic characteristics. Given its impact on pharmacotherapy efficacy, the lack of an association with pharmacotherapy choice suggests there is scope to use NMR status to optimise the selection and efficacy of smoking cessation pharmacotherapy. The unexpected association of NMR status with behavioural support should be explored further

“Let’s pull these technologies out of the ivory tower”: The politics, ethos, and ironies of participant-driven genomic research

This paper investigates how groups of ‘citizen scientists’ in non-traditional settings and primarily online networks claim to be challenging conventional genomic research processes and norms. Although these groups are highly diverse, they all distinguish their efforts from traditional university- or industry-based genomic research as being ‘participant-driven’ in one way or another. Participant-driven genomic research (PDGR) groups often work from ‘labs’ that consist of servers and computing devices as much as wet lab apparatus, relying on information-processing software for data-driven, discovery-based analysis rather than hypothesis-driven experimentation. We interviewed individuals from a variety of efforts across the expanding ecosystem of PDGR, including academic groups, start-ups, activists, hobbyists, and hackers, in order to compare and contrast how they relate their stated objectives, practices, and political and moral stances to institutions of expert scientific knowledge production. Results reveal that these groups, despite their diversity, share commitments to promoting alternative modes of housing, conducting, and funding genomic research and, ultimately, sharing knowledge. In doing so, PDGR discourses challenge existing approaches to research governance as well, especially the regulation, ethics, and oversight of human genomic information management. Interestingly, the reaction of the traditional genomics research community to this revolutionary challenge has not been negative: in fact, the community seems to be embracing the ethos espoused by PDGR, at the highest levels of science policy. As conventional genomic research assimilates the ethos of PDGR, the movement’s ‘democratizing’ views on research governance are likely to become normalized as well, creating new tensions for science policy and research ethics

Integrating genomics into clinical oncology: Ethical and social challenges from proponents of personalized medicine

The use of molecular tools to individualize health care, predict appropriate therapies and prevent adverse health outcomes has gained significant traction in the field of oncology, under the banner of “personalized medicine.” Enthusiasm for personalized medicine in oncology has been fueled by success stories of targeted treatments for a variety of cancers based on their molecular profiles. Though these are clear indications of optimism for personalized medicine, little is known about the ethical and social implications of personalized approaches in clinical oncology. The objective of this study is to assess how a range of stakeholders engaged in promoting, monitoring, and providing personalized medicine understand the challenges of integrating genomic testing and targeted therapies into clinical oncology. The study involved the analysis of in-depth interviews with 117 basic scientists, clinician-researchers, clinicians in private practice, health professional educators, representatives of funding agencies, medical journal editors, entrepreneurs, and insurers whose experiences and perspectives on personalized medicine span a wide variety of institutional and professional settings. Despite considerable enthusiasm for this shift, promoters, monitors and providers of personalized medicine identified four domains which will still provoke heightened ethical and social concerns: (1) informed consent for cancer genomic testing, (2) privacy, confidentiality, and disclosure of genomic test results, (3) access to genomic testing and targeted therapies in oncology, and (4) the costs of scaling up pharmacogenomic testing and targeted cancer therapies. These specific concerns are not unique to oncology, or even genomics. However, those most invested in the success of personalized medicine view oncologists’ responses to these challenges as precedent-setting because oncology is farther along the path of clinical integration of genomic technologies than other fields of medicine. This study illustrates that the rapid emergence of personalized medicine approaches in clinical oncology provides a crucial lens for identifying and managing potential frictions and pitfalls that emerge as health care paradigms shift in these directions

After the revolution? Ethical and social challenges in ‘personalized genomic medicine’

Personalized genomic medicine (PGM) is a goal that currently unites a wide array of biomedical initiatives, and is promoted as a ‘new paradigm for healthcare’ by its champions. Its promissory virtues include individualized diagnosis and risk prediction, more effective prevention and health promotion, and patient empowerment. Beyond overcoming scientific and technological hurdles to realizing PGM, proponents may interpret and rank these promises differently, which carries ethical and social implications for the realization of PGM as an approach to healthcare. We examine competing visions of PGM’s virtues and the directions in which they could take the field, in order to anticipate policy choices that may lie ahead for researchers, healthcare providers and the public

cGAS-STING Pathway Does Not Promote Autoimmunity in Murine Models of SLE

Detection of DNA is an important determinant of host-defense but also a driver of autoinflammatory and autoimmune diseases. Failure to degrade self-DNA in DNAseII or III(TREX1)-deficient mice results in activation of the cGAS-STING pathway. Deficiency of cGAS or STING in these models ameliorates disease manifestations. However, the contribution of the cGAS-STING pathway, relative to endosomal TLRs, in systemic lupus erythematosus (SLE) is controversial. In fact, STING deficiency failed to rescue, and actually exacerbated, disease manifestations in Fas-deficient SLE-prone mice. We have now extended these observations to a chronic model of SLE induced by the i.p. injection of TMPD (pristane). We found that both cGAS- and STING-deficiency not only failed to rescue mice from TMPD-induced SLE, but resulted in increased autoantibody production and higher proteinuria levels compared to cGAS STING sufficient mice. Further, we generated cGAS(KO)Fas(lpr) mice on a pure MRL/Fas(lpr) background using Crispr/Cas9 and found slightly exacerbated, and not attenuated, disease. We hypothesized that the cGAS-STING pathway constrains TLR activation, and thereby limits autoimmune manifestations in these two models. Consistent with this premise, mice lacking cGAS and Unc93B1 or STING and Unc93B1 developed minimal systemic autoimmunity as compared to cGAS or STING single knock out animals. Nevertheless, TMPD-driven lupus in B6 mice was abrogated upon AAV-delivery of DNAse I, implicating a DNA trigger. Overall, this study demonstrated that the cGAS-STING pathway does not promote systemic autoimmunity in murine models of SLE. These data have important implications for cGAS-STING-directed therapies being developed for the treatment of systemic autoimmunity

Genomic and microbiological analyses of iron acquisition pathways among respiratory and environmental nontuberculous mycobacteria from Hawai’i

As environmental opportunistic pathogens, nontuberculous mycobacteria (NTM) can cause severe and difficult to treat pulmonary disease. In the United States, Hawai’i has the highest prevalence of infection. Rapid growing mycobacteria (RGM) such as Mycobacterium abscessus and M. porcinum and the slow growing mycobacteria (SGM) including M. intracellulare subspecies chimaera are common environmental NTM species and subspecies in Hawai’i. Although iron acquisition is an essential process of many microorganisms, iron acquisition via siderophores among the NTM is not well-characterized. In this study, we apply genomic and microbiological methodologies to better understand iron acquisition via siderophores for environmental and respiratory isolates of M. abscessus, M. porcinum, and M. intracellulare subspecies chimaera from Hawai’i. Siderophore synthesis and transport genes, including mycobactin (mbt), mmpL/S, and esx-3 were compared among 47 reference isolates, 29 respiratory isolates, and 23 environmental Hawai’i isolates. Among all reference isolates examined, respiratory isolates showed significantly more siderophore pertinent genes compared to environmental isolates. Among the Hawai’i isolates, RGM M. abscessus and M. porcinum had significantly less esx-3 and mbt genes compared to SGM M. chimaera when stratified by growth classification. However, no significant differences were observed between the species when grown on low iron culture agar or siderophore production by the chrome azurol S (CAS) assay in vitro. These results indicate the complex mechanisms involved in iron sequestration and siderophore activity among diverse NTM species

Standardized reporting of the costs of management interventions for biodiversity conservation

Effective conservation management interventions must combat threats and deliver conservation benefits at costs that can be achieved within limited budgets. Considerable effort has focused on measuring the potential benefits of conservation interventions but explicit quantification of implementation costs has been rare. Even when costs have been quantified, haphazard and inconsistent reporting means that published values are difficult to interpret. This reporting deficiency hinders progress towards building a collective understanding of the costs of management interventions across projects, and thus limits our ability to identify efficient solutions to conservation problems or attract adequate funding. We address this challenge by proposing a standardized approach to describing costs reported for conservation interventions. These standards call for researchers and practitioners to ensure the cost data they collect and report on provide enough contextual information that readers and future users can interpret the data appropriately. We suggest these standards be adopted by major conservation organizations, conservation science institutions, and journals, so that cost reporting is comparable between studies. This would support shared learning and enhance our ability to identify and perform cost-effective conservation.Funding was provided by CEED (GDI and workshop), an ARC Laureate Fellowship (HPP, BM, VA and JM), Arcadia (WJS), the Natural Environment Research Council (LVD, NE/K015419/1; NE/N014472/1) and the Wildlife Conservation Society (AJP)

Mercury loading within the Selenga River basin and Lake Baikal, Siberia

Mercury (Hg) loading in Lake Baikal, a UNESCO world heritage site, is growing and poses a serious health concern to the lake’s ecosystem due to the ability of Hg to transform into a toxic form, known as methylmercury (MeHg). Monitoring of Hg into Lake Baikal is spatially and temporally sparse, highlighting the need for insights into historic Hg loading. This study reports measurements of Hg concentrations from water collected in August 2013 and 2014 from across Lake Baikal and its main inflow, the Selenga River basin (Russia, Mongolia). We also report historic Hg contamination using sediment cores taken from the south and north basins of Lake Baikal, and a shallow lake in the Selenga Delta. Field measurements from August 2013 and 2014 show high Hg concentrations in the Selenga Delta and river waters, in comparison to pelagic lake waters. Sediment cores from Lake Baikal show that Hg enrichment commenced first in the south basin in the late-19th century, and then in the north basin in the mid-20th century. Hg flux was also 20-fold greater in the south basin compared to the north basin sediments. Hg enrichment was greatest in the Selenga Delta shallow lake (Enrichment Ratio (ER) = 2.3 in 1994 CE), with enrichment occurring in the mid- to late-20th century. Local sources of Hg are predominantly from gold mining along the Selenga River, which have been expanding over the last few decades. More recently, another source is atmospheric deposition from industrial activity in Asia, due to rapid economic growth across the region since the 1980s. As Hg can bioaccumulate and biomagnify through trophic levels to Baikal’s top consumer, the world’s only truly freshwater seal (Pusa sibirica), it is vital that Hg input at Lake Baikal and within its catchment is monitored and controlled

Citizen science or scientific citizenship? Disentangling the uses of public engagement rhetoric in national research initiatives

Background: The language of “participant-driven research,” “crowdsourcing” and “citizen science” is increasingly being used to encourage the public to become involved in research ventures as both subjects and scientists. Originally, these labels were invoked by volunteer research efforts propelled by amateurs outside of traditional research institutions and aimed at appealing to those looking for more “democratic,” “patient-centric,” or “lay” alternatives to the professional science establishment. As mainstream translational biomedical research requires increasingly larger participant pools, however, corporate, academic and governmental research programs are embracing this populist rhetoric to encourage wider public participation. Discussion: We examine the ethical and social implications of this recruitment strategy. We begin by surveying examples of “citizen science” outside of biomedicine, as paradigmatic of the aspirations this democratizing rhetoric was originally meant to embody. Next, we discuss the ways these aspirations become articulated in the biomedical context, with a view to drawing out the multiple and potentially conflicting meanings of “public engagement” when citizens are also the subjects of the science. We then illustrate two uses of public engagement rhetoric to gain public support for national biomedical research efforts: its post-hoc use in the “care.data” project of the National Health Service in England, and its proactive uses in the “Precision Medicine Initiative” of the United States White House. These examples will serve as the basis for a normative analysis, discussing the potential ethical and social ramifications of this rhetoric. Summary: We pay particular attention to the implications of government strategies that cultivate the idea that members of the public have a civic duty to participate in government-sponsored research initiatives. We argue that such initiatives should draw from policy frameworks that support normative analysis of the role of citizenry. And, we conclude it is imperative to make visible and clear the full spectrum of meanings of “citizen science,” the contexts in which it is used, and its demands with respect to participation, engagement, and governance

Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability

Human ZIC1 (zinc finger protein of cerebellum 1), one of five homologs of the Drosophila pair-rule gene odd-paired, encodes a transcription factor previously implicated in vertebrate brain development. Heterozygous deletions of ZIC1 and its nearby paralog ZIC4 on chromosome 3q25.1 are associated with Dandy-Walker malformation of the cerebellum, and loss of the orthologous Zic1 gene in the mouse causes cerebellar hypoplasia and vertebral defects. We describe individuals from five families with heterozygous mutations located in the final (third) exon of ZIC1 (encoding four nonsense and one missense change) who have a distinct phenotype in which severe craniosynostosis, specifically involving the coronal sutures, and variable learning disability are the most characteristic features. The location of the nonsense mutations predicts escape of mutant ZIC1 transcripts from nonsense-mediated decay, which was confirmed in a cell line from an affected individual. Both nonsense and missense mutations are associated with altered and/or enhanced expression of a target gene, engrailed-2, in a Xenopus embryo assay. Analysis of mouse embryos revealed a localized domain of Zic1 expression at embryonic days 11.5-12.5 in a region overlapping the supraorbital regulatory center, which patterns the coronal suture. We conclude that the human mutations uncover a previously unsuspected role for Zic1 in early cranial suture development, potentially by regulating engrailed 1, which was previously shown to be critical for positioning of the murine coronal suture. The diagnosis of a ZIC1 mutation has significant implications for prognosis and we recommend genetic testing when common causes of coronal synostosis have been excluded