Co-producing Human and Animal Experimental Subjects: Exploring the Views of UK COVID-19 Vaccine Trial Participants on Animal Testing.

Preclinical (animal) testing and human testing of drugs and vaccines are rarely considered by social scientists side by side. Where this is done, it is typically for theoretically exploring the ethics of the two situations to compare relative treatment. In contrast, we empirically explore how human clinical trial participants understand the role of animal test subjects in vaccine development. Furthermore, social science research has only concentrated on broad public opinion and the views of patients about animal research, whereas we explore the views of a public group particularly implicated in pharmaceutical development: experimental subjects. We surveyed and interviewed COVID-19 vaccine trial participants in Oxford, UK, on their views about taking part in a vaccine trial and the role of animals in trials. We found that trial participants mirrored assumptions about legitimate reasons for animal testing embedded in regulation and provided insight into (i) the nuances of public opinion on animal research; (ii) the co-production of human and animal experimental subjects; (iii) how vaccine and medicine testing, and the motivations and demographics of clinical trial participants, change in an outbreak; and (iv) what public involvement can offer to science.

A multi-parameter approach to measurement of spontaneous myogenic contractions in human stomach: Utilization to assess potential modulators of myogenic contractions.

Electrical slow waves, generated by interstitial cells of Cajal (ICC), cause spontaneous contractions of human stomach. Software was developed to measure muscle tone and eleven different parameters defining these contractions in human stomach, displaying data as radar plots. A pilot study assessed the effects of potential modulators, selected from among compounds known to influence ICC activity; n = 4-7 each concentration tested/compound. Human distal stomach (corpus-antrum) muscle strips were suspended in tissue baths for measuring myogenic (non-neuronal) contractions in the presence of tetrodotoxin (10-6 M). Initial characterization: Contractions (amplitude 4 ± 0.4mN, frequency 3 ± 0.1 min-1, n = 49) were unchanged by ꭃ-conotoxin GVIA (10-7 M) or indomethacin (10-6 M) but abolished by nifedipine (10-4 M). Carbachol (10-7 M) increased contraction rate and amplitude; 10-6-10-5 M increased tone and caused large, irregular contractions. [Ca2+]imodulators: Ryanodine (10-5-10-4 M) increased muscle tone accompanied by inhibition of myogenic contractions. Xestospongin-C (10-6 M; IP3 channel inhibitor) had no effects. SERCA pump inhibitors, 2-APB and cycloplazonic acid (10-5-10-4 M) increased tone and myogenic contraction amplitude before abolishing contractions; thapsigargin was weakly active. CaCC blockers: MONNA and CaCCinh-A01 had little-or-no effects on tone but reduced myogenic contractions; MONNA (10-4 M) was more effective, reducing amplitude (77.8 ± 15.2%) and frequency. CaV3.1/3.2/3.3 channel block: Mibefradil reduced tone and myogenic contraction amplitude (pIC50 4.8 ± 0.9). Inward-rectifying K+-channel inhibitor: E-4031 (10-4 M) increased contraction duration (17.4 ± 5.8%). Conclusions: (1) Measurement of multiple parameters of myogenic contractions identified subtle differences between compounds, (2) only E-4031 and CaCC blockers influenced myogenic contractions, not muscle tone, (3) studies are needed with compounds with known and/or improved selectivity/potency for human targets affecting ICC functions.

Genetic interaction of Pax3 mutation and canonical Wnt signaling modulates neural tube defects and neural crest abnormalities.

Mouse models provide opportunities to investigate genetic interactions that cause or modify the frequency of neural tube defects (NTDs). Mutation of the PAX3 transcription factor prevents neural tube closure, leading to cranial and spinal NTDs whose frequency is responsive to folate status. Canonical Wnt signalling is implicated both in regulation of Pax3 expression and as a target of PAX3. This study investigated potential interactions of Pax3 mutation and canonical Wnt signalling using conditional gain- and loss-of-function models of ß-catenin. We found an additive effect of ß-catenin gain of function and Pax3 loss of function on NTDs and neural crest defects. ß-catenin gain of function in the Pax3 expression domain led to significantly increased frequency of cranial but not spinal NTDs in embryos that are heterozygous for Pax3 mutation, while both cranial and spinal neural tube closure were exacerbated in Pax3 homozygotes. Similarly, deficits of migrating neural crest cells were exacerbated by ß-catenin gain of function, with almost complete ablation of spinal neural crest cells and derivatives in Pax3 homozygous mutants. Pax3 expression was not affected by ß-catenin gain of function, while we confirmed that loss of function led to reduced Pax3 transcription. In contrast to gain of function, ß-catenin knockout in the Pax3 expression domain lowered the frequency of cranial NTDs in Pax3 null embryos. However, loss of function of ß-catenin and Pax3 resulted in spinal NTDs, suggesting differential regulation of cranial and spinal neural tube closure. In summary, ß-catenin function modulates the frequency of PAX3-related NTDs in the mouse.

Management of Velopharyngeal Insufficiency in Cleft Patients With and Without Multidisciplinary Team Care.

OBJECTIVE: To evaluate the effect of an American Cleft Palate-Craniofacial Association (ACPA)-approved multidisciplinary team on velopharyngeal insufficiency (VPI) diagnosis and treatment. DESIGN: Retrospective cohort setting; tertiary children's hospital patients; children with cleft palate repair identified through procedure codes. MAIN OUTCOME MEASURES: Velopharyngeal insufficiency diagnosis was assigned based on surgeon or team assessment. Age at diagnosis and surgery was recorded. Difference in age and rate of VPI diagnosis and surgery was analyzed with t test. Multivariate linear and logistic regression adjusted for confounding variables. RESULTS: Nine hundred forty patients were included with 71.5% cared for by an ACPA-approved multidisciplinary team. More (38.8% ) team care patients were found to have a diagnosis of VPI in comparison to 10% in independent care (P < .001). Team care was associated with an almost 6-fold increase in VPI diagnosis (P < .001). Team care was associated with a higher proportion of speech surgery (21% vs 10%, P < .001). Among children receiving team care, each visit was associated with 25% increased odds of being diagnosed with VPI (P < .001) and 20% increased odds of receiving speech surgery (P < .001). Age at VPI diagnosis and speech surgery were similar between groups (P = .55 and .29). DISCUSSION: Team care was associated with more accurate detection of VPI, resulting in more VPI speech therapy visits and surgical management. A higher number of team visits were similarly associated. CONCLUSION: Further studies of the clinical implication of timely and accurate VPI diagnosis, including quality of life assessments, are recommended to provide stronger guidance on team visit and evaluation planning.

Edge cases in animal research law: Constituting the regulatory borderlands of the UK's Animals (Scientific Procedures) Act.

This paper explores how the boundaries of the UK's Animals (Scientific Procedures) Act (A(SP)A) are constituted, as illustrative of the rising importance of legal procedures around animal research and how these are continuously being challenged and questioned. Drawing on empirical work in animal research communities, we consider how it is decided whether activities are undertaken for an "experimental or other scientific purpose". We do this by focusing on "edge cases", where debates occur about whether to include an activity within A(SP)A's remit. We demonstrate that the boundaries of animal research regulation in the UK are products of past and present decisions, dependencies, and social relationships. Boundaries are therefore not clear-cut and fixed, but rather flexible and changing borderlands. We particularly highlight the roles of: historical precedent; the management of risk, workload, and cost; institutional and professional identities; and research design in constituting A(SP)A's edges. In doing so, we demonstrate the importance of paying attention to how, in practice, animal law requires a careful balance between adhering to legal paragraphs and allowing for discretion. This in turn has real-world implications for what and how science is done, who does it, and how animals are used in its service.

AlphaB-crystallin regulates remyelination after peripheral nerve injury.

AlphaB-crystallin (αBC) is a small heat shock protein that is constitutively expressed by peripheral nervous system (PNS) axons and Schwann cells. To determine what role this crystallin plays after peripheral nerve damage, we found that loss of αBC impaired remyelination, which correlated with a reduced presence of myelinating Schwann cells and increased numbers of nonmyelinating Schwann cells. The heat shock protein also seems to regulate the cross-talk between Schwann cells and axons, because expected changes in neuregulin levels and ErbB2 receptor expression after PNS injury were disrupted in the absence of αBC. Such dysregulations led to defects in conduction velocity and motor and sensory functions that could be rescued with therapeutic application of the heat shock protein in vivo. Altogether, these findings show that αBC plays an important role in regulating Wallerian degeneration and remyelination after PNS injury.

Animal research nexus: a new approach to the connections between science, health and animal welfare.

Animals used in biological research and testing have become integrated into the trajectories of modern biomedicine, generating increased expectations for and connections between human and animal health. Animal research also remains controversial and its acceptability is contingent on a complex network of relations and assurances across science and society, which are both formally constituted through law and informal or assumed. In this paper, we propose these entanglements can be studied through an approach that understands animal research as a nexus spanning the domains of science, health and animal welfare. We introduce this argument through, first, outlining some key challenges in UK debates around animal research, and second, reviewing the way nexus concepts have been used to connect issues in environmental research. Third, we explore how existing social sciences and humanities scholarship on animal research tends to focus on different aspects of the connections between scientific research, human health and animal welfare, which we suggest can be combined in a nexus approach. In the fourth section, we introduce our collaborative research on the animal research nexus, indicating how this approach can be used to study the history, governance and changing sensibilities around UK laboratory animal research. We suggest the attention to complex connections in nexus approaches can be enriched through conversations with the social sciences and medical humanities in ways that deepen appreciation of the importance of path-dependency and contingency, inclusion and exclusion in governance and the affective dimension to research. In conclusion, we reflect on the value of nexus thinking for developing research that is interdisciplinary, interactive and reflexive in understanding how accounts of the histories and current relations of animal research have significant implications for how scientific practices, policy debates and broad social contracts around animal research are being remade today.

Changes in neuromuscular structure and functions of human colon during ageing are region-dependent.

OBJECTIVE: To determine if human colonic neuromuscular functions decline with increasing age. DESIGN: Looking for non-specific changes in neuromuscular function, a standard burst of electrical field stimulation (EFS) was used to evoke neuronally mediated (cholinergic/nitrergic) contractions/relaxations in ex vivomuscle strips of human ascending and descending colon, aged 35-91 years (macroscopically normal tissue; 239 patients undergoing cancer resection). Then, to understand mechanisms of change, numbers and phenotype of myenteric neurons (30 306 neurons stained with different markers), densities of intramuscular nerve fibres (51 patients in total) and pathways involved in functional changes were systematically investigated (by immunohistochemistry and use of pharmacological tools) in elderly (≥70 years) and adult (35-60 years) groups. RESULTS: With increasing age, EFS was more likely to evoke muscle relaxation in ascending colon instead of contraction (linear regression: n=109, slope 0.49%±0.21%/year, 95% CI), generally uninfluenced by comorbidity or use of medications. Similar changes were absent in descending colon. In the elderly, overall numbers of myenteric and neuronal nitric oxide synthase-immunoreactive neurons and intramuscular nerve densities were unchanged in ascending and descending colon, compared with adults. In elderly ascending, not descending, colon numbers of cell bodies exhibiting choline acetyltransferase immunoreactivity increased compared with adults (5.0±0.6 vs 2.4±0.3 neurons/mm myenteric plexus, p=0.04). Cholinergically mediated contractions were smaller in elderly ascending colon compared with adults (2.1±0.4 and 4.1±1.1 g-tension/g-tissue during EFS; n=25/14; p=0.04); there were no changes in nitrergic function or in ability of the muscle to contract/relax. Similar changes were absent in descending colon. CONCLUSION: In ascending not descending colon, ageing impairs cholinergic function.

Convergence in Reports of Adolescents' Psychopathology: A Focus on Disorganized Attachment and Reflective Functioning.

Although convergence in parent-youth reports of adolescent psychopathology is critical for treatment planning, research documents a pervasive lack of agreement in ratings of adolescents' symptoms. Attachment insecurity (particularly disorganized attachment) and impoverished reflective functioning (RF) are 2 theoretically implicated predictors of low convergence that have not been examined in the literature. In a cross-sectional investigation of adolescents receiving inpatient psychiatric treatment, we examined whether disorganized attachment and low (adolescent and parent) RF were associated with patterns of convergence in adolescent internalizing and externalizing symptoms. Compared with organized adolescents, disorganized adolescents had lower parent-youth convergence in reports of their internalizing symptoms and higher convergence in reports of their externalizing symptoms; low adolescent self-focused RF was associated with low convergence in parent-adolescent reports of internalizing symptoms, whereas low adolescent global RF was associated with high convergence in parent-adolescent reports of externalizing symptoms. Among adolescents receiving inpatient psychiatric treatment, disorganized attachment and lower RF were associated with weaker internalizing symptom convergence and greater externalizing symptom convergence, which if replicated, could inform assessment strategies and treatment planning in this setting.

Murine neutrophils treated with alphaB-crystallin reduce IL-12p40 production by dendritic cells.

Neutrophils are essential in the fight against invading pathogens. They utilize antimicrobial effector mechanisms, such as phagocytosis, release of proteases and other antimicrobial products, robust oxidative bursts and neutrophil extracellular traps to combat infections. Neutrophils also modulate immune responses through the production of eicosanoids, cytokines and chemokines, as well as via direct communication with other immune cells. This system of high-intensity offense against pathogens is exquisitely balanced through regulation to limit damage to host tissue. Unfortunately, the control of neutrophils is not failproof. In cases of sterile injury, autoimmunity and even during an infection, neutrophils can cause tissue destruction and become detrimental to the host. For that reason, there is a need to find means to regulate the aberrant activation of these cells. We found that alphaB-crystallin (αBC), a heat-shock protein known to have anti-inflammatory abilities, affects certain properties of mouse neutrophils that subsequently influence the pro-inflammatory state of antigen-presenting cells (APCs). More specifically, αBC mediated small but significant increases in the levels of IL-10 and matrix metalloproteinase 8, and altered hydrogen peroxide secretion by stimulated neutrophils. Further, the heat-shock protein influenced the communication between neutrophils and dendritic cells by decreasing the production of pro-inflammatory cytokines, specifically IL-12p40, by the APCs. αBC could thus contribute to dampening neutrophil inflammatory responses by impacting the effect of neutrophils on other immune cells.

CRYAB plays a role in terminating the presence of pro-inflammatory macrophages in the older, injured mouse peripheral nervous system.

Evidence indicates that dysfunction of older Schwann cells and macrophages contributes to poor regeneration of more mature peripheral nervous system (PNS) neurons after damage. Since the underlying molecular factors are largely unknown, we investigated if CRYAB, a small heat shock protein that is expressed by Schwann cells and axons and whose expression declines with age, impacts prominent deficits in the injured, older PNS including down-regulation of cholesterol biosynthesis enzyme genes, Schwann cell dysfunction, and macrophage persistence. Following sciatic nerve transection injury in 3- and 12-month-old wildtype and CRYAB knockout mice, we found by bulk RNA sequencing and RT-PCR, that while gene expression of cholesterol biosynthesis enzymes is markedly dysregulated in the aging, injured PNS, CRYAB is not involved. However, immunohistochemical staining of crushed sciatic nerves revealed that more macrophages of the pro-inflammatory but not immunosuppressive phenotype persisted in damaged 12-month-old knockout nerves. These pro-inflammatory macrophages were more efficient at engulfing myelin debris. CRYAB thus appears to play a role in resolving pro-inflammatory macrophage responses after damage to the older PNS.

COVID-19-Related Employment Disruptions and Increased Financial Burden Among Survivors of Adolescent and Young Adult Cancer.

Background: Financial burden is a major concern for survivors of adolescent and young adult (AYA) cancers. We identified if employment disruptions during the COVID-19 pandemic affected AYA survivors' financial burden. Methods: AYAs who were enrolled in a cancer patient navigation program were e-mailed a survey in fall 2020. Survey items included sociodemographics, employment disruption, and two measures of financial burden: COmprehensive Score for Financial Toxicity (COST) and material and behavioral financial hardship items (for any reason, COVID-19 induced, cancer induced). Financial burden outcomes were dichotomized at the median (COST = 21; financial hardship = 3). The association of employment disruptions and sociodemographics with financial burden was assessed using multivariable logistic regression models. Results: Reduced hours/job loss was reported by 24.0% of 341 participants. Survivors with a high school education or less (odds ratio [OR]: 2.70; 95% confidence interval [CI]: 1.21-6.03) or who had decreased hours or job loss (OR: 3.97; 95% CI: 2.01-7.84) had greater odds for high financial toxicity. Reduced hours/job loss was the only factor associated with high material and behavioral financial hardship for both any reason (OR: 2.75; 95% CI: 1.41-5.33) and owing to COVID-19 (OR: 4.98; 95% CI: 2.28-10.92). Cancer treatment since March 2020 was associated with cancer-induced high material and behavioral financial hardship (OR: 3.31; 95% CI: 1.96-5.58). Conclusion: Employment disruptions owing to the COVID-19 pandemic, lower education levels, and cancer treatment were associated with high financial burden among AYA cancer survivors. Our findings suggest the need for multilevel interventions to identify and address financial burden among vulnerable cancer survivors.

Simultaneous sequencing of genetic and epigenetic bases in DNA.

DNA comprises molecular information stored in genetic and epigenetic bases, both of which are vital to our understanding of biology. Most DNA sequencing approaches address either genetics or epigenetics and thus capture incomplete information. Methods widely used to detect epigenetic DNA bases fail to capture common C-to-T mutations or distinguish 5-methylcytosine from 5-hydroxymethylcytosine. We present a single base-resolution sequencing methodology that sequences complete genetics and the two most common cytosine modifications in a single workflow. DNA is copied and bases are enzymatically converted. Coupled decoding of bases across the original and copy strand provides a phased digital readout. Methods are demonstrated on human genomic DNA and cell-free DNA from a blood sample of a patient with cancer. The approach is accurate, requires low DNA input and has a simple workflow and analysis pipeline. Simultaneous, phased reading of genetic and epigenetic bases provides a more complete picture of the information stored in genomes and has applications throughout biomedicine.

When research animals become pets and pets become research animals: care, death, and animal classification.

This paper explores what happens to care, and decisions about ending and extending life, when research animals become pets and pets become research animals. To do this, we draw on in-depth qualitative research on (i) rehoming of laboratory animals, (ii) veterinary clinical research, and (iii) the role of the Named Veterinary Surgeon (NVS) in UK animal research. We begin by exploring how (in theory and practice) the ethical, affective, and practical elements of care are split in the research laboratory. We then investigate arguments for and against ending and extending animal life via clinical research and rehoming, highlighting how these activities bring norms and dilemmas around animal death in the laboratory and veterinary clinic to the fore. We conclude by demonstrating the value of investigating borders between animal categories for understanding dilemmas around care and death, and for contributing to emerging literatures within geography around animal care, death, and categorisation. Key contributions of our work include highlighting: how care roles can be split; the importance of considering speculative and in-practice elements of care; the context-dependency and multiplicity of practices of killing in the veterinary clinic and laboratory; and the flexibility and changing nature of animal categories.

Este artículo explora lo que sucede con el cuidado y las decisiones sobre el final y la extensión de la vida cuando los animales de investigación se convierten en mascotas y las mascotas se convierten en animales de investigación. Para hacer esto, nos basamos en una investigación cualitativa a profundidad sobre (i) el realojamiento de animales de laboratorio, (ii) la investigación clínica veterinaria y (iii) el papel del Cirujano Veterinario Designado (CVD o NVS por sus siglas en inglés) en la investigación con animales en el Reino Unido. Comenzamos explorando cómo (en la teoría y la práctica) los elementos éticos, afectivos y prácticos del cuidado se dividen en el laboratorio de investigación. Luego investigamos los argumentos a favor y en contra de terminar y extender la vida animal a través de la investigación clínica y el realojamiento, destacando cómo estas actividades ponen de manifiesto las normas y los dilemas en torno a la muerte animal en el laboratorio y la clínica veterinaria. Concluimos demostrando el valor de investigar las fronteras entre las categorías de animales para comprender los dilemas sobre el cuidado y la muerte, y para contribuir a las literaturas emergentes dentro de la geografía sobre el cuidado, la muerte y la categorización de los animales. Las contribuciones clave de nuestro trabajo incluyen destacar: cómo se pueden dividir los roles de cuidado; la importancia de considerar elementos especulativos y de práctica de la atención; la dependencia del contexto y la multiplicidad de prácticas de matanza en la clínica veterinaria y el laboratorio; y la flexibilidad y naturaleza cambiante de las categorías de animales.

Cet article étudie ce qu'il advient du care et des décisions concernant l'arrêt ou l'extension de la vie, quand les animaux de recherche deviennent animaux de compagnie et que les animaux de compagnie deviennent animaux de recherche. Pour ce faire, nous nous appuyons sur une recherche qualitative approfondie sur (i) l'adoption d'animaux de laboratoire (ii) la recherche clinique vétérinaire, et (iii) le rôle du chirurgien vétérinaire nommé (NVS - Named Veterinary Surgeon) dans la recherche animale au Royaume-Uni. Nous commençons en explorant la manière dont, en théorie et en pratique, les éléments éthiques, affectifs et pratiques du care sont divisés dans le laboratoire de recherche. Nous passons ensuite en revue les arguments pour ou contre l'arrêt ou l'extension de la vie animale par le biais de la recherche clinique et l'adoption, en soulignant la façon dont ces activités amènent au premier plan les normes et les dilemmes autour de la mort animal en laboratoire et dans les cliniques vétérinaires. Nous concluons en démontrant la valeur de l'étude des frontières entre les catégories d'animaux pour comprendre les problèmes entourant le care et la mort, et pour contribuer aux recherches naissantes dans la géographie concernant le care, la mort et la catégorisation des animaux. Les contributions majeures de nos travaux comprennent la mise en évidence de: la manière dont les rôles de care peuvent être divisés; l'importance de la prise en compte d'éléments de care spéculatifs et dans la pratique ; le rapport au contexte et la multiplicité des pratiques de mise à mort dans les cliniques et les laboratoires vétérinaires ; et la flexibilité et la nature changeante des catégories d'animaux.

Ixazomib With or Without Rituximab Following Maintenance Autologous Stem Cell Transplant in Mantle Cell Lymphoma: A Single-Center Phase I Trial.

BACKGROUND: Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard first-line treatment for fit patients with mantle cell lymphoma (MCL). We conducted a single-center phase I trial investigating post-transplant maintenance with ixazomib, an oral proteasome inhibitor. METHODS: Patients enrolled between days +70 and +180 post ASCT. Patients received ixazomib per dose cohort on days 1, 8, and 15 of each 28-day cycle for up to 10 cycles. During recruitment, published phase III data reported a survival benefit with rituximab maintenance, so all subsequent patients received ixazomib 4 mg at the same schedule along with rituximab 375 mg/m2 on day 1 of cycles 1, 3, 5, 7, and 9. All patients were in complete remission at enrollment. RESULTS: Seven patients received ixazomib monotherapy; 1 dose limiting toxicity (grade 3 neutropenia) occurred at dose level 2 (4 mg). Five patients received combination Ixazomib plus rituximab, with 2 experiencing DLTs (both Grade 4 neutropenia). Grade 3-4 neutropenia, lymphopenia, and thrombocytopenia occurred in 57%, 8%, and 8% of patients, respectively. Non-hematologic adverse events (AE) included nausea (42%), peripheral neuropathy (42%), and abdominal discomfort (33%), all of which were grade 1 or 2 in severity. There were no infectious AEs. With a median follow up of 46 months, all patients are alive and in complete remission. CONCLUSION: The trial was closed to further accrual due to high rates of treatment-related myelosuppression. The current dose and schedule of ixazomib, especially when combined with rituximab, results in unacceptable hematologic toxicity when administered as post-transplant maintenance in MCL. Ixazomib maintenance micro abstract: The authors conducted a phase I study investigating the use of ixazomib, an oral proteasome inhibitor, with or without rituximab in patients with mantle cell lymphoma in first remission following chemoimmunotherapy and autologous stem cell transplantation. All patients treated on study remain in complete remission with a median follow-up of 46 months, but the study was closed early due to a high rate of hematologic adverse events.

Synergistic augmentation of rhythmic myogenic contractions of human stomach by arginine vasopressin and adrenaline: Implications for the induction of nausea.

BACKGROUND AND PURPOSE: Nausea is associated with the hormonal secretion of vasopressin and adrenaline, although their actions in inducing nausea is poorly understood. Here, we have investigated their actions on human stomach muscle. EXPERIMENTAL APPROACH: Muscle strips were suspended in tissue baths and neuronal-/non-neuronally-mediated contractions were measured. Custom software analysed eight motility parameters defining spontaneous phasic non-neuronally mediated contractions. Receptor distributions were assessed by qPCR and immunofluorescence. KEY RESULTS: V1A receptors and α1 -adrenoceptors were located on muscle as well as interstitial cells of Cajal (ICCs). Myogenic contractions of human proximal and distal stomach (respectively, 2.6 ± 0.1 and 2.7 ± 0.0 per minute; n = 44) were larger in the distal area (1.1 ± 0.1 and 5.0 ± 0.1 mN), developing relatively slowly (proximal) or rapidly (distal). Vasopressin caused tonic (proximal) or short-lived (distal) increases in muscle tone and increased myogenic contraction amplitude, frequency and rate (acting at V1A receptors; thresholds 10-11 -10-10  M); by contrast, cholinergically mediated contractions were unaffected. Oxytocin acted similarly to vasopressin but less potently, at OT receptors). Adrenaline increased (10-10 -10-5  M; α1 -adrenoceptors) and decreased (≥10-6  M; ß-adrenoceptors) muscle tone and enhanced/reduced myogenic contractions. Cholinergically mediated contractions were reduced (α2 -adrenoceptors). Combined, vasopressin (10-9  M) and adrenaline (10-8  M) increased muscle tone and phasic myogenic activity in a synergistic manner. CONCLUSIONS AND IMPLICATIONS: Vasopressin and adrenaline increased human gastric tone and myogenic contraction amplitude, rate of contraction and frequency. In combination, their actions were further increased in a synergistic manner. Such activity may promote nausea.

Out of the laboratory, into the field: perspectives on social, ethical and regulatory challenges in UK wildlife research.

Drawing on insights from qualitative social science research, this paper aims to prompt reflection on social, ethical and regulatory challenges faced by scientists undertaking invasive animal research in the field and propose ways of addressing these challenges to promote good care for animals and environments. In particular, we explore challenges relating to the management of (i) relationships with publics and stakeholders, who may be present at field sites or crucial to research success; (ii) ethical considerations not present in the laboratory, such as the impacts of research on populations and ecosystems; (iii) working under an array of regulations, which may operate in accordance with competing ethical principles or objectives; and (iv) relationships with regulators (especially vets), which may involve disagreements over ethics and expertise, especially because regulators may be more accustomed to overseeing research in the laboratory than the field. We argue that flexibility-at a personal and policy level-and respect for others' expertise emerged as two key ways of negotiating ethical challenges, fostering positive working relationships and promoting good care for individual animals and broader ecosystems. While our analysis focuses on the UK, we propose that many of these lessons are broadly applicable to international contexts. This article is part of the theme issue 'Measuring physiology in free-living animals (Part II)'.

Hybrid apes in the Anthropocene: Burden or asset for conservation?

Conservationists often view hybrid animals as problematic, at least if anthropogenic influence caused the intermixing to occur. However, critics propose that humans should respect non-human autonomy, reject and accept the creatures they have helped to create.Based on two case studies of our own ethological, genetic and ethnographic research about chimpanzee and orangutan subspecies hybrids, we assess what, if anything, should be done about such animals. We consider problems posed by cross-bred apes relating to: (a) Breeding-Do hybrids really experience reduced reproductive success? How are population-level concerns and welfare of individual animals balanced in conservation breeding? (b) Essentialism-Are anti-hybrid arguments based on essentialist or purist thinking? Does essentialism vary by conservation context? (c) Pragmatism-How do socio-economic circumstances influence whether hybrids are embraced or ignored? Does the erosion of 'untouched nature' render hybrids more important?We show that answers to these questions are complex and context-specific, and that therefore decisions should be made on a case-by-case basis. For example, we find that anti-hybrid arguments are essentialist in some cases (e.g. ape management in zoos) but not in others (e.g. ape reintroduction). Thus, rather than present recommendations, we conclude by posing nine questions that conservationists should ask themselves when making decisions about taxonomic hybrids. ​ A free Plain Language Summary can be found within the Supporting Information of this article.

Getting to grips with wildlife research by citizen scientists: What role for regulation?

Wildlife research by citizen scientists, involving the capture and handling of animals, provides clear scientific benefits, but also potential risks to animal welfare. We explore debates about how best to regulate such work to ensure that it is undertaken in an ethical manner.We focus on the UK as a case study, drawing on qualitative research and stakeholder engagement events. We show that because trapping and marking of certain species requires minimal licensing, training and justification, some argue for increased formal regulation to minimise risks to animal welfare. However, others have reflected on the already complex regulatory landscape affecting wildlife research, and have expressed concern that introducing additional formal regulations could potentially make citizen science working with wildlife more difficult. Informal regulation could therefore offer a preferable alternative.We set out three steps that could be taken to open up conversations about ethics and regulation of wildlife-focussed citizen science, in the UK and elsewhere: (a) take stock of wildlife-focussed citizen science in terms of numbers and harms to animal welfare; (b) assess the state of formal regulations and consider reforms; and (c) consider informal regulations as alternatives or additions to formal regulations.

Efficacy and Safety of Ertugliflozin in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea: A Sub-Study of VERTIS CV.

INTRODUCTION: VERTIS CV is the cardiovascular outcome trial for the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin. A sub-study was conducted to assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately glycemic-controlled on metformin and a sulfonylurea (SU). METHODS: Patients with T2DM, established atherosclerotic cardiovascular disease (ASCVD), and an HbA1c of 7.0-10.5% on stable metformin (≥ 1500 mg/day) and moderate to high SU doses were randomly assigned to once-daily ertugliflozin (5 or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ertugliflozin on HbA1c compared with placebo and to evaluate safety following 18 weeks of treatment. Key secondary endpoints included changes in fasting plasma glucose (FPG), body weight (BW), blood pressure (BP), and the proportion of patients achieving HbA1c < 7%. RESULTS: Of the 8246 patients enrolled in VERTIS CV, 330 were eligible for this sub-study (ertugliflozin 5 mg, n = 100; ertugliflozin 15 mg, n = 113; placebo, n = 117). This subgroup had a mean (SD) age of 63.2 (8.4) years and T2DM duration of 11.4 (7.4) years. At week 18, ertugliflozin 5 mg and 15 mg were each associated with significantly greater least squares (LS) mean reductions from baseline in HbA1c relative to placebo (placebo-adjusted LS mean [95% CI] - 0.66% [- 0.89, - 0.43] and - 0.75% [- 0.98, - 0.53], respectively, p < 0.001 for each dose vs placebo). Ertugliflozin significantly reduced FPG and BW compared with placebo (p < 0.001), but not systolic BP. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ertugliflozin 5 mg and 15 mg, and placebo groups. The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo). CONCLUSIONS: In patients with T2DM and ASCVD, ertugliflozin added to metformin and SU improved glycemic control, reduced BW, and was generally well tolerated. TRIAL REGISTRATION: VERTIS CV ClinicalTrials.gov identifier, NCT01986881.