One health research in Northern Tanzania – challenges and progress

East Africa has one of the world’s fastest growing human populations—many of whom are dependent on livestock—as well as some of the world’s largest wildlife populations. Humans, livestock, and wildlife often interact closely, intimately linking human, animal, and environmental health. The concept of One Health captures this interconnectedness, including the social structures and beliefs driving interactions between species and their environments. East African policymakers and researchers are recognising and encouraging One Health research, with both groups increasingly playing a leading role in this subject area. One Health research requires interaction between scientists from different disciplines, such as the biological and social sciences and human and veterinary medicine. Different disciplines draw on norms, methodologies, and terminologies that have evolved within their respective institutions and that may be distinct from or in conflict with one another. These differences impact interdisciplinary research, both around theoretical and methodological approaches and during project operationalisation. We present experiential knowledge gained from numerous ongoing projects in northern Tanzania, including those dealing with bacterial zoonoses associated with febrile illness, foodborne disease, and anthrax. We use the examples to illustrate differences between and within social and biological sciences and between industrialised and traditional societies, for example, with regard to consenting procedures or the ethical treatment of animals. We describe challenges encountered in ethical approval processes, consenting procedures, and field and laboratory logistics and offer suggestions for improvement. While considerable investment of time in sensitisation, communication, and collaboration is needed to overcome interdisciplinary challenges inherent in One Health research, this can yield great rewards in paving the way for successful implementation of One Health projects. Furthermore, continued investment in African institutions and scientists will strengthen the role of East Africa as a world leader in One Health research

“Attending to History” in Major System Change in Healthcare in England: Specialist Cancer Surgery Service Reconfiguration

BACKGROUND: The reconfiguration of specialist hospital services, with service provision concentrated in a reduced number of sites, is one example of major system change (MSC) for which there is evidence of improved patient outcomes. This paper explores the reconfiguration of specialist oesophago-gastric (OG) cancer surgery services in a large urban area of England (Greater Manchester, GM), with a focus on the role of history in this change process and how reconfiguration was achieved after previous failed attempts. METHODS: This study draws on qualitative research from a mixed-methods evaluation of the reconfiguration of specialist cancer surgery services in GM. Forty-six interviews with relevant stakeholders were carried out, along with ~160 hours of observations at meetings and the acquisition of ~300 pertinent documents. Thematic analysis using deductive and inductive approaches was undertaken, guided by a framework of 'simple rules' for MSC. RESULTS: Through an awareness of, and attention to, history, leaders developed a change process which took into account previous unsuccessful reconfiguration attempts, enabling them to reduce the impact of potentially challenging issues. Interviewees described attending to issues involving competition between provider sites, change leadership, engagement with stakeholders, and the need for a process of change resilient to challenge. CONCLUSION: Recognition of, and response to, history, using a range of perspectives, enabled this reconfiguration. Particularly important was the way in which history influenced and informed other aspects of the change process and the influence of stakeholder power. This study provides further learning about MSC and the need for a range of perspectives to enable understanding. It shows how learning from history can be used to enable successful change

An artificial therapist (manage your life online) to support the mental health of youth: Co-design and case series

Background: The prevalence of child and adolescent mental health issues is increasing faster than the number of services available, leading to a shortfall. Mental health chatbots are a highly scalable method to address this gap. Manage Your Life Online (MYLO) is an artificially intelligent chatbot that emulates the method of levels therapy. Method of levels is a therapy that uses curious questioning to support the sustained awareness and exploration of current problems. Objective: This study aimed to assess the feasibility and acceptability of a co-designed interface for MYLO in young people aged 16 to 24 years with mental health problems. Methods: An iterative co-design phase occurred over 4 months, in which feedback was elicited from a group of young people (n=7) with lived experiences of mental health issues. This resulted in the development of a progressive web application version of MYLO that could be used on mobile phones. We conducted a case series to assess the feasibility and acceptability of MYLO in 13 young people over 2 weeks. During this time, the participants tested MYLO and completed surveys including clinical outcomes and acceptability measures. We then conducted focus groups and interviews and used thematic analysis to obtain feedback on MYLO and identify recommendations for further improvements. Results: Most participants were positive about their experience of using MYLO and would recommend MYLO to others. The participants enjoyed the simplicity of the interface, found it easy to use, and rated it as acceptable using the System Usability Scale. Inspection of the use data found evidence that MYLO can learn and adapt its questioning in response to user input. We found a large effect size for the decrease in participants’ problem-related distress and a medium effect size for the increase in their self-reported tendency to resolve goal conflicts (the proposed mechanism of change) in the testing phase. Some patients also experienced a reliable change in their clinical outcome measures over the 2 weeks. Conclusions: We established the feasibility and acceptability of MYLO. The initial outcomes suggest that MYLO has the potential to support the mental health of young people and help them resolve their own problems. We aim to establish whether the use of MYLO leads to a meaningful reduction in participants’ symptoms of depression and anxiety and whether these are maintained over time by conducting a randomized controlled evaluation trial

Erratum: Author Correction: Midbrain Circuit Regulation of Individual Alcohol Drinking Behaviors in Mice (Nature Communications (2017) 8 1 (2220))

The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML versions of the Article

Use of directed acyclic graphs (DAGs) to identify confounders in applied health research: review and recommendations

Abstract Background Directed acyclic graphs (DAGs) are an increasingly popular approach for identifying confounding variables that require conditioning when estimating causal effects. This review examined the use of DAGs in applied health research to inform recommendations for improving their transparency and utility in future research. Methods Original health research articles published during 1999–2017 mentioning ‘directed acyclic graphs’ (or similar) or citing DAGitty were identified from Scopus, Web of Science, Medline and Embase. Data were extracted on the reporting of: estimands, DAGs and adjustment sets, alongside the characteristics of each article’s largest DAG. Results A total of 234 articles were identified that reported using DAGs. A fifth (n = 48, 21%) reported their target estimand(s) and half (n = 115, 48%) reported the adjustment set(s) implied by their DAG(s). Two-thirds of the articles (n = 144, 62%) made at least one DAG available. DAGs varied in size but averaged 12 nodes [interquartile range (IQR): 9–16, range: 3–28] and 29 arcs (IQR: 19–42, range: 3–99). The median saturation (i.e. percentage of total possible arcs) was 46% (IQR: 31–67, range: 12–100). 37% (n = 53) of the DAGs included unobserved variables, 17% (n = 25) included ‘super-nodes’ (i.e. nodes containing more than one variable) and 34% (n = 49) were visually arranged so that the constituent arcs flowed in the same direction (e.g. top-to-bottom). Conclusion There is substantial variation in the use and reporting of DAGs in applied health research. Although this partly reflects their flexibility, it also highlights some potential areas for improvement. This review hence offers several recommendations to improve the reporting and use of DAGs in future research

The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity

Discovery of new small molecules that can activate distinct programmed cell death pathway is of significant interest as a research tool and for the development of novel therapeutics for pathological conditions such as cancer and infectious diseases. The small molecule raptinal was discovered as a pro-apoptotic compound that can rapidly trigger apoptosis by promoting the release of cytochrome c from the mitochondria and subsequently activating the intrinsic apoptotic pathway. As raptinal is very effective at inducing apoptosis in a variety of different cell types in vitro and in vivo, it has been used in many studies investigating cell death as well as the clearance of dying cells. While examining raptinal as an apoptosis inducer, we unexpectedly identified that in addition to its pro-apoptotic activities, raptinal can also inhibit the activity of caspase-activated Pannexin 1 (PANX1), a ubiquitously expressed transmembrane channel that regulates many cell death-associated processes. By implementing numerous biochemical, cell biological and electrophysiological approaches, we discovered that raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Surprisingly, raptinal was found to inhibit cleavage-activated PANX1 via a mechanism distinct to other well-described PANX1 inhibitors such as carbenoxolone and trovafloxacin. Furthermore, raptinal also interfered with PANX1-regulated apoptotic processes including the release of the 'find-me' signal ATP, the formation of apoptotic cell-derived extracellular vesicles, as well as NLRP3 inflammasome activation. Taken together, these data identify raptinal as the first compound that can simultaneously induce apoptosis and inhibit PANX1 channels. This has broad implications for the use of raptinal in cell death studies as well as in the development new PANX1 inhibitors

Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors

Examining the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacological, and optical tools allow activation of neurons with exquisite spatiotemporal resolution; however, the inaccessibility to light of widely distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacologically inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single-neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased locomotion, stereotypy, and limbic seizures. These results demonstrate a powerful chemical-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo