Where exactly do the social and behavioural sciences fit in One Health?

At its core, One Health promotes multidisciplinary cooperation amongst researchers and practitioners to improve the effectiveness and management of complex problems raised by the interplay of human, animal and environment interactions. Contemporary One Health literature has identified reducing disciplinary barriers as key to progress in the field, along with addressing the notable absence of social sciences from One Health frameworks, among other priorities. Efforts to position social scientists as experts on behaviour change and health decision-making has helped to articulate a concrete role for progressing One Health collaborations. Yet, there are other equally valuable functions the social scientist has in understanding complex systems, like One Health. We make explicit the multiple and diverse knowledge contributions the social sciences and humanities can make to progressing the One Health agenda. Articulating these more clearly invites a broader set of interdisciplinary perspectives to One Health discussions, allowing for stronger connections between sectors, actors, disciplines, and sub-systems. This perspective piece identifies a range of entry points for researchers and practitioners to better utilize the potential contributions social sciences and humanities scholars can make to One Health goals.

The New South Wales Mouse Plague 2020-2021: A One Health description.

A mouse plague occurred in Eastern Australia from spring 2020 to winter 2021, impacting an area of around 180,000 km2. It harmed human physical and psychological health, damaged the natural and built environment, and endangered farmed, domestic and native animals. However, the mouse plague was overshadowed by the COVID-19 pandemic, especially as the end of the plague coincided with the arrival and surge of the COVID-19 delta strain in rural New South Wales (NSW). In this article, we systematically overview the multiple impacts of the plague and highlight their complex interactions. Using a One Health framework, we comprehensively review the i) human, ii) animal and iii) environmental impacts including economic dimensions. Given the damage that the mouse plague caused to infrastructure, we consider the environment from two perspectives: the natural and the built environment. This One Health description of the 2020-2021 mouse plague identifies priorities for preparedness, response and recovery at local, regional land levels to inform response and management of future mouse plague events in Australia. It also highlights the need for ongoing collaboration between researchers and practitioners in the human, animal and environmental health sectors.

Blood RNA-sequencing across the continuum of ANA-positive autoimmunity reveals insights into initiating immunopathology.

OBJECTIVE: Mechanisms underpinning clinical evolution to systemic lupus erythematosus (SLE) from preceding antinuclear antibodies (ANA) positivity are poorly understood. This study aimed to understand blood immune cell transcriptional signatures associated with subclinical ANA positivity, and progression or non-progression to SLE. METHODS: Bulk RNA-sequencing of peripheral blood mononuclear cells isolated at baseline from 35 ANA positive (ANA+) subjects with non-diagnostic symptoms was analysed using differential gene expression, weighted gene co-expression network analysis, deconvolution of cell subsets and functional enrichment analyses. ANA+ subjects, including those progressing to classifiable SLE at 12 months (n=15) and those with stable subclinical ANA positivity (n=20), were compared with 15 healthy subjects and 18 patients with SLE. RESULTS: ANA+ subjects demonstrated extensive transcriptomic dysregulation compared with healthy controls with reduced CD4+naïve T-cells and resting NK cells, but higher activated dendritic cells. B-cell lymphopenia was evident in SLE but not ANA+ subjects. Two-thirds of dysregulated genes were common to ANA+ progressors and non-progressors. ANA+ progressors showed elevated modular interferon signature in which constituent genes were inducible by both type I interferon (IFN-I) and type II interferon (IFN-II) in vitro. Baseline downregulation of mitochondrial oxidative phosphorylation complex I components significantly associated with progression to SLE but did not directly correlate with IFN modular activity. Non-progressors demonstrated more diverse cytokine profiles. CONCLUSIONS: ANA positivity, irrespective of clinical trajectory, is profoundly dysregulated and transcriptomically closer to SLE than to healthy immune function. Metabolic derangements and IFN-I activation occur early in the ANA+ preclinical phase and associated with diverging transcriptomic profiles which distinguish subsequent clinical evolution.

Deconvolution of whole blood transcriptomics identifies changes in immune cell composition in patients with systemic lupus erythematosus (SLE) treated with mycophenolate mofetil.

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically and biologically heterogeneous autoimmune disease. We explored whether the deconvolution of whole blood transcriptomic data could identify differences in predicted immune cell frequency between active SLE patients, and whether these differences are associated with clinical features and/or medication use. METHODS: Patients with active SLE (BILAG-2004 Index) enrolled in the BILAG-Biologics Registry (BILAG-BR), prior to change in therapy, were studied as part of the MASTERPLANS Stratified Medicine consortium. Whole blood RNA-sequencing (RNA-seq) was conducted at enrolment into the registry. Data were deconvoluted using CIBERSORTx. Predicted immune cell frequencies were compared between active and inactive disease in the nine BILAG-2004 domains and according to immunosuppressant use (current and past). RESULTS: Predicted cell frequency varied between 109 patients. Patients currently, or previously, exposed to mycophenolate mofetil (MMF) had fewer inactivated macrophages (0.435% vs 1.391%, p = 0.001), naïve CD4 T cells (0.961% vs 2.251%, p = 0.002), and regulatory T cells (1.858% vs 3.574%, p = 0.007), as well as a higher proportion of memory activated CD4 T cells (1.826% vs 1.113%, p = 0.015), compared to patients never exposed to MMF. These differences remained statistically significant after adjusting for age, gender, ethnicity, disease duration, renal disease, and corticosteroid use. There were 2607 differentially expressed genes (DEGs) in patients exposed to MMF with over-representation of pathways relating to eosinophil function and erythrocyte development and function. Within CD4 + T cells, there were fewer predicted DEGs related to MMF exposure. No significant differences were observed for the other conventional immunosuppressants nor between patients according disease activity in any of the nine organ domains. CONCLUSION: MMF has a significant and persisting effect on the whole blood transcriptomic signature in patients with SLE. This highlights the need to adequately adjust for background medication use in future studies using whole blood transcriptomics.

Xanthogranulomatous cholecystitis: diagnostic complexity and review of the literature.

We report the case of a 39-year-old male presenting with acute onset vomiting and diarrhoea. Initially treated empirically for gastroenteritis, imaging later confirmed a complicated episode of cholecystitis with fistular formation and intra-abdominal cyst. Following cholecystectomy, histology confirmed a case of xanthogranulomatous cholecystitis (XGC). This paper presents a detailed summary of the condition alongside a literature review of all available episodes of XGC since 2017 with the aim of highlighting diagnostic conclusions regarding the nature of the disease and its clinical manifestations.

Rapid efficacy of anifrolumab across multiple subtypes of recalcitrant cutaneous lupus erythematosus parallels changes in discrete subsets of blood transcriptomic and cellular biomarkers.

BACKGROUND: Observations with rituximab suggest B-cell independent mechanisms of cutaneous lupus erythematosus (CLE) in systemic lupus erythematosus (SLE), especially discoid lupus erythematosus (DLE). Type-I interferon receptor blockade with anifrolumab shows efficacy in SLE, but efficacy for cutaneous disease of specific morphologies has not been studied. Interferon has pleotropic immune effects and it is unknown which of these are critical to therapeutic response. OBJECTIVES: We evaluated clinical efficacy and quality-of-life impact of type-I interferon-blockade in: (i) rituximab-refractory CLE; (ii) DLE and other morphologies and (iii) transcriptomic and flow cytometric biomarkers. METHODS: We conducted a prospective single-centre study of anifrolumab in refractory mucocutaneous SLE. CLE Disease Area and Severity Index (CLASI) activity score, health-related quality of life, 96-probe TaqMan® gene expression analysis capturing key SLE blood transcriptome signatures, and eight-colour flow cytometry were undertaken at baseline, 1, 3 and 6 months. RESULTS: Seven patients [DLE (n = 5), chilblain lupus erythematosus (n = 1), subacute CLE (n = 1)] were evaluated. The median number of prior therapies was six (range 3-15), including rituximab in six of seven patients. Median CLASI-A showed rapid and sustained improvement from 17 at baseline to 6 (P = 0.016) at 1 month and 0 (P < 0.001) by 3 months. The median percentage reduction in CLASI-A at 3 months was 60%. Significant improvements were observed in Dermatology Life Quality Index scores (P < 0.001), EuroQol 5D visual analogue scale (P = 0.002) and LupusQoL fatigue, image and planning domains (P ≤ 0.05). One patient discontinued treatment owing to severe herpes zoster. Clinical responses paralleled discrete suppression of interferon-stimulated genes (ISGs) from SLE blood transcriptome module M1.2 with more varied downregulation in other interferon modules. Myeloid and inflammation-annotated genes remained upregulated throughout treatment. Intermediate monocytes (CD14++CD16+) reduced to normal levels during therapy (P = 0.014), while other flow subsets showed no substantive changes. CONCLUSIONS: These data indicate rapid efficacy of anifrolumab in DLE and rituximab-resistant CLE. Response is associated with suppression of a subset of ISGs and decline in intermediate monocytes. Suppression of all ISGs or the wider SLE blood transcriptome is not required for response.

Is Public Engagement in Bioengineering and Synthetic Biology Improving Research Outcomes?

Engaging diverse publics on the acceptability of large-scale biology applications such as gene drives is held in high regard by the international research community. The development of gene drives to suppress invasive and pest species and improvements to the sustainability of food systems are examples of integrative biology applications in engineering and ecology with the potential for large-scale research impact. Despite a global collective intention to ensure disruptive technologies are in broad alignment with wider social and public values, evidence of applied research organizations integrating the knowledge acquired from social research is hard to find. Concrete mechanisms to ensure public perspectives affect science decision-making are yet to emerge. We offer avenues for making inroads in what we identify as a remaining gap in public engagement research in the fields of synthetic biology and bioengineering.

Gene Expression and Autoantibody Analysis Revealing Distinct Ancestry-Specific Profiles Associated With Response to Rituximab in Refractory Systemic Lupus Erythematosus.

OBJECTIVE: Gene expression profiles are associated with the clinical heterogeneity of systemic lupus erythematosus (SLE) but are not well studied as biomarkers for therapy. We studied gene expression and response to rituximab in a multiethnic UK cohort who were refractory to standard therapy. METHODS: We evaluated baseline expression levels of transcripts known to associate with clinical features of SLE using a 96-probe TaqMan array and whole blood samples from 213 patients with active SLE who had been prospectively enrolled in the British Isles Lupus Assessment Group (BILAG) Biologics Register. We measured autoantibodies using immunoprecipitation and enzyme-linked immunosorbent assays. We determined responses to first-cycle rituximab at 6 months from treatment start in 110 SLE patients by assessing BILAG 2004 disease activity. RESULTS: Interferon gene expression scores were lower in patients of European ancestry than in all other ancestry groups. The relationship between blood interferon gene expression scores and scores annotated to plasmablasts, neutrophils, myeloid lineage, inflammation, and erythropoiesis differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified responses to rituximab that were not explained by sociodemographic and clinical variables, with responses lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression levels across all signatures (P < 0.001). Clusters in European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters were associated with U1 RNP/Sm antibodies. CONCLUSION: Ancestry appears central to the immunologic and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity, and transcriptional signatures could each assist in predicting the effectiveness of B cell depletion therapies.

Three synthetic biology applications and their paths to impact in Australia: Cane toads, bacteriophages, and biomining microbes.

Synthetic biology [synbio] applications have the potential to assist in addressing significant global health and environmental challenges. Australian research institutes are investing in formative research to develop synbio technologies capable of meeting these challenges. Alongside the laboratory research, investigating the broader social, institutional, and ethical considerations that synbio presents has been a priority. We conducted targeted qualitative research to uncover the barriers and opportunities for a range of multisectoral stakeholders identified as potential end-users of the science under development. The research provides insights into the research implementation environment for three synthetic biology applications: (1) gene editing cane toads (Rhinella marina) to reduce their environmental impact; (2) engineering bacteriophages to combat antimicrobial resistance in humans; and (3) engineering microbes to improve biomining efficiency in the mining industry. In-depth interviews (N = 23) with government, research and civil society representatives revealed key challenges in the impact pathway for each application. The strongest themes uncovered during interviews related to perceived negative public attitudes towards genetic technologies, a lack of investment in critical research infrastructure, unclear regulatory pathways and the presence of a strong social and environmental imperative underpinning technology development. These findings reveal specific entry points for further engagement with the most immediate end-users of synbio. Separate from research on public attitudes to synbio, the cases highlight the various hurdles to achieving research impact, according to experts who will likely use, approve or invest in these applications in the future. The themes uncovered inform avenues for strengthening engagement and research coordination in Australia and elsewhere.

Affecting behavioural change through empowerment: conceptual insights from theory and agricultural case studies in South Asia.

Affecting behavioural change is a common underlying goal across environmental and agricultural sciences, from climate change mitigation and adaptation, biodiversity conservation, water management, to crop diversification. However, many projects fail to drive or sustain change despite sound science and good intentions. This paper draws on existing theories of behavioural change to construct a conceptual framework that explores pathways to initiate and sustain change through the lens of empowerment, self-efficacy and agency. The framework is demonstrated with case studies from a project in India and Bangladesh that examined social inclusion of marginalised and poor farmers in the context of intensifying agriculture. The framework and case studies highlight that a number of conditions are needed to affect meaningful change including that target beneficiaries are suitably motivated, believe in their own capability and power to enact change and have access to the necessary resources. We propose the framework as a tool to help project teams explore the underlying elements of the process of change when designing, implementing and assessing agricultural or environmental projects and interventions. We contend that behavioural and social change needs to be explicitly fostered in such endeavours to achieve better and longer-term outcomes for the people and environment. Supplementary Information: The online version contains supplementary material available at 10.1007/s10113-022-01939-7.

Genetically engineered heat-resistant coral: An initial analysis of public opinion.

Rising seawater temperatures are contributing to coral degradation in the Great Barrier Reef. Synthetic biology technologies offer the potential to enhance coral resilience to higher water temperatures. To explore what the public think of genetically engineered coral as a future solution, qualitative responses to an open-ended question in a survey of 1,148 of the Australian public were analysed. More respondents supported the technology (59%) than did not (11%). However, a considerable proportion indicated moderate support (29%). Participants commented about the (moral) right to interfere with nature and uncertainty regarding the consequences of implementing the technology. Participants also mentioned the need to take responsibility and act to save the reef, as well as the benefits likely to result from implementing the technology. Other themes included a desire for further testing and proof, more information, and tight regulation and controls when introducing the technology.

Applying Early Intervention Strategies to Autoimmune Skin Diseases. Is the Window of Opportunity Preclinical? A Dermato-Rheumatology Perspective.

Many inflammatory skin diseases exhibit a chronic course with unsatisfactory long-term outcomes. Insights into early intervention approaches in other autoimmune contexts could improve the trajectory of lifelong diseases in terms of sustained remission or minimal disease activity, reduced requirement for therapy and medical resource use, and improved QoL. In both rheumatoid arthritis (RA) and psoriatic arthritis (PsA), we have learned that the timing and intensity of early interventions can influence later outcomes. Investigation into early RA, PsA, and systemic lupus erythematosus has shown that the optimal window of opportunity may even extend into asymptomatic preclinical phases of diseases. Notably, early and preclinical diseases may have pathogenic mechanisms and therapeutic targets that differ from those of the established disease. In this paper, we review the literature on these insights and discuss how similar research and therapeutic strategies may be investigated in cutaneous autoimmunity. We highlight the contribution of skin-resident cells to diseases that were previously thought to be initiated in the primary and secondary lymphoid organs of the immune system. We focus on two dermato‒rheumatology conditions-lupus and psoriasis-which share the commonality that effective early cutaneous disease therapy may have far-reaching implications on abrogating potentially severe systemic disease.

Easy-BILAG: a new tool for simplified recording of SLE disease activity using BILAG-2004 index.

OBJECTIVE: BILAG-2004 index is a comprehensive disease activity instrument for SLE but administrative burden and potential frequency of errors limits its use in routine practice. We aimed to develop a tool for more accurate, time-efficient scoring of BILAG-2004 index with full fidelity to the existing instrument. METHODS: Frequency of BILAG-2004 items was collated from a BILAG-biologics registry (BILAG-BR) dataset. Easy-BILAG prototypes were developed to address known issues affecting speed and accuracy. After expert verification, accuracy and usability of the finalized Easy-BILAG was validated against standard format BILAG-2004 in a workbook exercise of 10 case vignettes. Thirty-three professionals ranging in expertise from 14 UK centres completed the validation exercise. RESULTS: Easy-BILAG incorporates all items present in ≥5% BILAG-BR records, plus full constitutional and renal domains into a rapid single page assessment. An embedded glossary and colour-coding assists domain scoring. A second page captures rarer manifestations when needed. In the validation exercise, Easy-BILAG yielded higher median scoring accuracy (96.7%) than standard BILAG-2004 documentation (87.8%, P = 0.001), with better inter-rater agreement. Easy-BILAG was completed faster (59.5 min) than the standard format (80.0 min, P = 0.04) for 10 cases. An advantage in accuracy was observed with Easy-BILAG use among general hospital rheumatologists (91.3 vs 75.0, P = 0.02), leading to equivalent accuracy as tertiary centre rheumatologists. Clinicians rated Easy-BILAG as intuitive, convenient, and well adapted for routine practice. CONCLUSION: Easy-BILAG facilitates more rapid and accurate scoring of BILAG-2004 across all clinical settings, which could improve patient care and biologics prescribing. Easy-BILAG should be adopted wherever BILAG-2004 assessment is required.

Effects of knowledge and emotion on support for novel synthetic biology applications.

There is sometimes an inherent assumption that the logical head will overrule the emotional heart in matters of science and technology. However, the literature on decision making under risk and uncertainty suggests that emotional responses may be more potent. A representative sample of Australians participated in a large, national, online survey (n = 8037), in which we measured the influence of knowledge and emotion in predicting support for possible synthetic biology (synbio) solutions to conservation, environmental, and industrial problems. A hierarchical regression model was used to examine the relative influence of affect- and emotion-related factors beyond the influence of knowledge factors in predicting support for synbio solutions. Subsequently, interaction analyses were conducted to examine the potentially moderating role of emotions in the knowledge-support relationship. There was 64% variance in overall support for synbio solutions (R2 = 0.64, p < 0.001). The most influential predictor of support in the model was positive emotion. Feeling hopeful, excited, and curious toward a synbio technology was related to greater overall support for the development of that technology. The second strongest set of predictors was affect-related measures that evaluate the technology as bad or good, harmful or beneficial, and risky or safe. Positive emotion and an assessment that the technology was good significantly moderated the effect of knowledge on support. These findings suggest that, at least initially, people are more likely to be guided by their emotions when considering support for synbio technologies, which has implications for how researchers design and implement engagement and communication strategies more broadly.

Efectos del Conocimiento y las Emociones sobre el Respaldo a las Aplicaciones Novedosas de la Biología Sintética Resumen A veces existe la suposición intrínseca de que la mente lógica anulará al corazón emocional cuando se trata de temas de ciencia y tecnología. Sin embargo, la literatura sobre la toma de decisiones durante situaciones de riesgo e incertidumbre sugiere que las respuestas emocionales pueden ser más potentes. Una muestra representativa de australianos (n = 8,037) participó en una encuesta en línea realizada a nivel nacional y a gran escala. En esta encuesta medimos la influencia del conocimiento y las emociones sobre la predicción del respaldo a posibles soluciones de biología sintética (synbio) para problemas ambientales, industriales y de conservación. Usamos un modelo de regresión jerárquica para examinar la influencia relativa de los factores relacionados con el afecto o las emociones más allá de la influencia de los factores de conocimiento sobre las predicciones del respaldo a las soluciones synbio. Después realizamos análisis de interacción para examinar el papel potencialmente moderador de las emociones en la relación conocimiento-respaldo. Hubo un 64% de varianza en el respaldo general a las soluciones synbio (R2 = 0.64, p < 0.001). El pronosticador más influyente del respaldo en el modelo fue la emoción positiva. La sensación de sentirse esperanzado, emocionado y curioso debido a la tecnología synbio estuvo relacionada con un mayor respaldo generalizado para el desarrollo de aquella tecnología. El segundo conjunto más fuerte de pronosticadores fueron las medidas relacionadas con el afecto que valoran a la tecnología como buena o mala, dañina o benéfica, y riesgosa o segura. Una emoción positiva y una valoración de que la tecnología era buena moderaron significativamente el efecto del conocimiento sobre el respaldo. Estos hallazgos sugieren que, por lo menos al inicio, las personas tienen mayor probabilidad de ser guiadas por sus emociones cuando consideran el respaldo a las tecnologías synbio, lo cual tiene consecuencias para cómo los investigadores diseñan e implementan las estrategias de participación y comunicación más extensamente.

Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial.

BACKGROUND: Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity. METHODS: In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells. RESULTS: The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-γ ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ. CONCLUSIONS: An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab. TRIAL REGISTRATION: The trial was registered with the U.S. National Institutes of Health (NIH) Clinical Trials Registry (ClinicalTrials.gov identifier NCT02390063).

Engagement and social acceptance in genome editing for human benefit: Reflections on research and practice in a global context.

While there are both practical and ethical reasons for public engagement in science and innovation, real-world detailed examples of engagement practice and the lessons to come from these are still hard to find. This paper showcases three contextually diverse case studies of engagement practice. Case 1 recounts the experiences of a government-funded initiative to involve scientists and policy makers as science communicators for the purpose of engaging the Argentine public on gene editing. Case 2 describes the research methodologies used to elicit diverse stakeholder views in the face of political uncertainty and institutional distrust in India. Finally, case 3 unpacks the tensions and gaps with existing international guidelines for ensuring local voices are respected in community decision-making in Burkina Faso. Each case shares its own compelling rationale for selecting the engagement method chosen and details the challenges encountered along the way. Each case shares its vision for creating legitimate opportunities for broader societal involvement in the planning, conduct and delivery of responsible science. These cases demonstrate the nuances, sensitivities and challenges of engaging with publics and broader stakeholders in discussions about genome editing for human benefit.

The Promises and Realities of Integration in Synthetic Biology: A View From Social Science.

Discussions about the responsible advancement of synthetic biology science are at fever pitch. Commentators from across the globe are calling for greater integrated science investments and more inclusive governance processes in the development and implementation of these potentially disruptive technologies. We take stock of the promises and realities of science integration by sharing our experiences of embarking on this very challenge in Australia. We conclude by offering suggestions for bringing about the enabling conditions for improved integration across the natural and social sciences. Four key actions are articulated to help pivot synthetic biology toward a more integrated scientific endeavor: (a) formalizing inclusivity from inception to project conclusion; (b) valuing differing philosophical positions as a strength rather than a barrier; (c) accepting that integration takes persistence and communication but is immensely rewarding; and (d) promoting meaningful interactions, such as pursuing joint opportunities, co-designing and co-publishing research. We argue that these actions are key enablers for realizing science integration in synthetic biology.

Biological control of pests and a social model of animal welfare.

This paper considers the sociocultural implications of biological pest control that sit at the cusp of managing an invasive species for conservation or productivity (i.e. a 'natural enemy') and socially driven 'manipulating life' arguments. We consider the role of perceived humaneness or, more accurately, animal welfare as it relates to managing invasive species from a scientific and social perspective. In order to highlight and articulate particular nuances and standards across different pest control contexts, we use three case examples (feral cats, wild rabbits, and invasive cane toads) and explore where biological pest control and animal welfare interests intersect. The paper summarises key scientific welfare concerns and then extends the literature to also examine key social characteristics of each pest management scenario, including lay perceptions of animal welfare, the sociocultural context that pests exist within, and overarching psychological factors contributing to public sentiment, including perceived risks. The subsequent descriptive model presented is useful in articulating core sociocultural beliefs relative to each case and how these antecedent associations and attitudes about an animal influence subsequent beliefs about a pest management strategy and ultimately acceptance of the management approach. The model can inform invasive species management policies and highlight key sociocultural factors likely to influence public responses. The model also informs interdisciplinary science designed to develop acceptable and socially responsible biocontrol strategies that consider public perceptions of animal welfare and cultural appropriateness.

Antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis: a randomised controlled pilot and feasibility study.

BACKGROUND: Little evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis. METHODS: We did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197. FINDINGS: Of 138 patients referred to the study, 75 were recruited and randomly assigned-26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44·5 weeks (IQR 26-51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (-5·65 [95% CI -10·37 to -0·93]; p=0·019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (-4·52 [95% CI -9·30 to 0·26]; p=0·064) or between the antipsychotics and CBT groups (-1·13 [95% CI -5·81 to 3·55]; p=0·637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3·22 [95% CI 0·58 to 5·87]; p=0·017) or antipsychotics plus CBT (3·99 [95% CI 1·36 to 6·64]; p=0·003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group). INTERPRETATION: A head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis. FUNDING: National Institute for Health Research.