Quality of life beyond measure: Advanced cancer patients, wellbeing and medicinal cannabis.

Experiences of advanced cancer are assembled and (re)positioned with reference to illness, symptoms and maintaining 'wellbeing'. Medical cannabis is situated at a borderline in this and the broader social domain: between stigmatised and normalised; recreational and pharmaceutical; between perception, experience, discourse and scientific proof of benefit. Yet, in the hyper-medicalised context of randomised clinical trials (RCTs), cancer, wellbeing and medical cannabis are narrowly assessed using individualistic numerical scores. This article attends to patients' perceptions and experiences at this borderline, presenting novel findings from a sociological sub-study embedded within RCTs focused on the use of medical cannabis for symptom relief in advanced cancer. Through a Deleuzo-Guattarian-informed framework, we highlight the fragmentation and reassembling of bodies and propose body-situated experiences of wellbeing in the realm of advanced cancer. Problematising 'biopsychosocial' approaches that centre an individualised disconnected patient body in understandings of wellbeing, experiences of cancer and potential treatments, our findings foreground relational affect and embodied experience, and the role of desire in understanding what wellbeing is and can be. This also underpins and enables exploration of the affective reassembling ascribed to medical cannabis, with particular focus on how it is positioned within RCTs.

Imperatives of health or happiness: Narrative constructions of long-term smoking after undergoing lung screening.

Tobacco control policies reinforce a health imperative that positions citizens as duty-bound to manage their health by abstaining from or quitting smoking. Limited attention is paid to the repercussions - especially for lung screening - of anti-smoking rhetoric emphasising individual responsibility. Drawing on interviews with 27 long-term smokers involved in an international lung screening trial, this study analysed Australian smokers' narratives of smoking. By attending to stigma and the use of public health rhetoric within personal narratives, we show how narratives underscoring individual responsibility for quitting were layered with conflicting explanations of biological responsibility and normative expectations. Ironically, narratives of individual responsibility potentially undermine smoking cessation. In positioning smokers as responsible for their own healthy choices, such rhetoric also positions smokers as responsible for managing their emotional health, which some did through smoking. Thus, anti-smoking campaigns pit the neoliberal imperative of health against the happiness imperative. These findings have implications for the design and delivery of lung screening campaigns. They also support calls to move beyond health messaging emphasising individual choice, towards acknowledging the moral power of structures and public health campaigns to discipline citizens in unintended ways.

'What price do you put on your health?': Medical cannabis, financial toxicity and patient perspectives on medication access in advanced cancer.

INTRODUCTION: Following 2016 legislation permitting limited access to cannabis for research and medicinal purposes, the number of randomized clinical trials (RCTs) investigating the effectiveness of medicinal cannabis (MC) on symptom burden relief in cancer contexts has increased in Australia. This study aimed to understand the perceptions, hopes and concerns of people with advanced cancer regarding the future availability and regulation of MC in Australia. METHODS: This qualitative study draws on semistructured interviews conducted between February 2019 and October 2020 in Brisbane, Australia, as part of an MC RCT substudy. Interviews were undertaken on 48 patients with advanced cancer in palliative care eligible to participate in an MC trial (n = 26 participated in an RCT; n = 2 participated in a pilot study; n = 20 declined). Interviews included a discussion of patients' decision-making regarding trial participation, concerns about MC and perceptions of future availability, including cost. Transcribed interviews were analysed inductively and abductively, informed by constructivist thematic analysis conventions. RESULTS: Overall, participants supported making MC legally accessible as a prescription-only medication. Fear of financial toxicity, however, compromised this pathway. Steep posttrial costs of accessing MC prompted several people to decline trial participation, and others to predict-if found effective-that many would either access MC through alternative pathways or reduce their prescribed dosage to enable affordable access. CONCLUSIONS: These findings suggest that-despite a relatively robust universal healthcare system-Australians are potentially vulnerable to and fearful of financial toxicity. Prevalent in the United States, financial toxicity occurs when disadvantaged cancer patients access necessary but expensive medications with lasting consequences: bankruptcy, ongoing anxiety and cancer worry. Interview transcripts indicate that financial fears-and the systems sustaining them-may pose a threat to RCT completion and to equitable access to legal MC. Such findings support calls for embedding qualitative substudies and community partnerships within RCTs, while also suggesting the importance of subsidisation to overcoming injustices. PATIENT OR PUBLIC CONTRIBUTION: A patient advisory committee informed RCT design. This qualitative substudy foregrounds patients' decision-making, perceptions and experiences.

Medicinal cannabis in palliative medicine: lessons learnt from randomised controlled trials.

OBJECTIVES: To detail important lessons learnt while conducting several large, medicinal cannabis (MC) randomised clinical trials in a palliative cancer population. METHODS: Investigators involved in these trials had several meetings to agree on the major lessons learnt and how the various challenges could be mitigated in the future. RESULTS: The lessons were sorted into separate categories: patient confidentiality, family dynamics, driving, cost, unfounded beliefs, accessing specific MC products, trial funding, telehealth and COVID-19, and miscellaneous issues. CONCLUSION: Using MC as the intervention arm in such trials entails some unique regulatory, logistical and other challenges. This short report presents key lessons learnt in conducting these randomised controlled trials in a palliative care population for the benefit of future investigators planning similar trials in a similar patient population.

Using a qualitative sub-study to inform the design and delivery of randomised controlled trials on medicinal cannabis for symptom relief in patients with advanced cancer.

BACKGROUND: Recruitment for randomised controlled trials in palliative care can be challenging; disease progression and terminal illness underpin high rates of attrition. Research into participant decision-making in medicinal cannabis randomised controlled trials (RCTs) is very limited. Nesting qualitative sub-studies within RCTs can identify further challenges to participation, informing revisions to study designs and recruitment practices. This paper reports on findings from a qualitative sub-study supporting RCTs of medicinal cannabis for symptom burden relief in patients with advanced cancer in one Australian city. METHODS: Semi-structured qualitative interviews were conducted with 48 patients with advanced cancer, eligible to participate in a medicinal cannabis RCT (n=28 who consented to participate in an RCT; n=20 who declined). An iterative and abductive approach to thematic analysis and data collection fostered exploration of barriers and enablers to participation. RESULTS: Key enablers included participants' enthusiasm and expectations of medicinal cannabis as beneficial (to themselves and future patients) for symptom management, especially after exhausting currently approved options, and a safer alternative to opioids. Some believed medicinal cannabis to have anti-cancer effects. Barriers to participation were the logistical challenges of participating (especially due to driving restrictions and fatigue), reluctance to interfere with an existing care plan, cost, and concerns about receiving the placebo and the uncertainty of the benefit. Some declined due to concerns about side-effects or a desire to continue accessing cannabis independent of the study. CONCLUSIONS: The findings support revisions to subsequent medicinal cannabis RCT study designs, namely, omitting a requirement that participants attend weekly hospital appointments. These findings highlight the value of embedding qualitative sub-studies into RCTs. While some challenges to RCT recruitment are universal, others are context (population, intervention, location) specific. A barrier to participation found in research conducted elsewhere-stigma-was not identified in the current study. Thus, findings have important implications for those undertaking RCTs in the rapidly developing context of medical cannabis.

Emotions and lung cancer screening: Prioritising a humanistic approach to care.

Low-dose computed tomography lung cancer screening has mortality benefits. Yet, uptake has been low. To inform strategies to better deliver and promote screening, in 2018, we interviewed 27 long-term smokers immediately following lung cancer screening in Australia, prior to receiving scan results. Existing lung screening studies employ the Health Belief Model. Reflecting growing acknowledgement of the centrality of emotions to screening uptake, we draw on psychological and sociological theories on emotions to thematically and abductively analyse the emotional dimensions of lung cancer screening, with implications for screening promotion and delivery. As smokers, interviewees described feeling stigmatised, with female participants internalising and male participants resisting stigma. Guilt and fear related to lung cancer were described as screening motivators. The screening itself elicited mild positive emotions. Notably, interviewees expressed gratitude for the care implicitly shown through lung screening to smokers. More than individual risk assessment, findings suggest lung screening campaigns should prioritise emotions. Peer workers have been found to increase cancer screening uptake in marginalised communities, however the risk to confidentiality-especially for female smokers-limits its feasibility in lung cancer screening. Instead, we suggest involving peer consultants in developing targeted screening strategies that foreground emotions. Furthermore, findings suggest prioritising humanistic care in lung screening delivery. Such an approach may be especially important for smokers from low socioeconomic backgrounds, who perceive lung cancer screening and smoking as sources of stigma and face a higher risk of dying from lung cancer and lower engagement with screening.

Physiotherapists Both Reproduce and Resist Biomedical Dominance when Working With People With Low Back Pain: A Qualitative Study Towards New Praxis.

Despite recommendations to incorporate physical and psychosocial factors when providing care for people with back pain, research suggests that physiotherapists continue to focus on biological aspects. This study investigated how interpersonal and institutional norms influence this continued enactment of the biological aspects of management. We used theoretically-driven analysis, drawing from Foucauldian notions of power, to analyse 28 ethnographic observations of consultations and seven group discussions with physiotherapists. Analysis suggested that physiotherapy training established expectations of what a physiotherapist 'should' focus on, and institutional circumstances strongly drew the attention of physiotherapists towards biological aspects. Resistance to these forces was possible when, for example, physiotherapists reflected upon their practice, used silences and pauses during consultations, and actively collaborated with patients. These circumstances facilitated use of non-biomedical management approaches. Findings may assist physiotherapists to rework the enduring normative focus on biomedical aspects of care when providing care for patients with back pain.

Surprise Reveals the Affective-Moral Economies in Cancer Illness Narratives.

Emotions, like joy and sorrow, feature in illness narratives, dramatizing stories of becoming: sick, well, controlled, in control. However, brief emotions, such as surprise, have received limited analytic attention in cancer illness narratives. Drawing on 20 interviews with 11 participants with diverse cancer diagnoses, along with the 455 photographs they produced for this study, we address the complex interactions between discourse, societal expectations, and perceptions in moral-affective economies. Tracing the emergence, deployment, and silencing of surprise provided an avenue to explore connections between affect, morality, advocacy, and philanthropy. We show how surprise works to deny uncertainties couched in individual risk, and situate cancer causation within the logics of anticipation, (re)producing socio-cultural etiology narratives. Attending to surprise reveals how some cancers are situated as individual responsibilities, with restricted access to compassion and collective resources. Thus, we interrogate the affective-moral economy underpinning cancer illness narratives, and surprise's pivotal role in its analysis.

Emotionally reflexive labour in end-of-life communication.

Within palliative care, clear and open communication about death is encouraged. Euphemisms are discouraged as threats to promoting clear understanding of the prognosis; to opening communication about what a good death means to individual patients and families; and to fostering collaborative planning aimed at achieving this 'good death'. Principles of patient-centred and culturally competent care, however, which reflect trends of individualisation, plurality and multiculturalism that are characteristic of late modernity, encourage respect for and support of patients' and families' preferences. These may include wishes to avoid open communication, preferences for euphemisms, and definitions of a 'good death' that vary from the practitioner's, and within families. The aim of this study was to examine how physicians navigate these competing priorities. Analysis is based on interviews with 23 doctors, ranging in experience from medical students through to senior palliative care specialists, and eight recorded observations of palliative care multidisciplinary team meetings with 52 clinicians collected in 2017 at two hospitals in one Australian metropolitan area. Findings show that synonyms familiar to clinicians are often used to communicate prognoses in multidisciplinary meetings. In communication with patients and families, doctors rely on emotional and cultural cues to decipher the preferred terminology and response. Drawing on a late modern re-imagination of emotion management, we conceptualise the work performed in this context as emotionally reflexive labour. These findings suggest that blanket protocols for direct communication overlook the complexity of end-of-life communication in an era where a 'good death' is understood to be culturally relative.

Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation.

Hepatitis C virus (HCV) infection remains a major cause of hepatic inflammation and liver disease. HCV triggers NLRP3 inflammasome activation and interleukin-1ß (IL-1ß) production from hepatic macrophages, or Kupffer cells, to drive the hepatic inflammatory response. Here we examined HCV activation of the NLRP3 inflammasome signaling cascade in primary human monocyte derived macrophages and THP-1 cell models of hepatic macrophages to define the HCV-specific agonist and cellular processes of inflammasome activation. We identified the HCV core protein as a virion-specific factor of inflammasome activation. The core protein was both necessary and sufficient for IL-1ß production from macrophages exposed to HCV or soluble core protein alone. NLRP3 inflammasome activation by the HCV core protein required calcium mobilization linked with phospholipase-C activation. Our findings reveal a molecular basis of hepatic inflammasome activation and IL-1ß release triggered by HCV core protein.

Domain-specific physical activity and affective wellbeing among adolescents: an observational study of the moderating roles of autonomous and controlled motivation.

BACKGROUND: Abundant evidence demonstrates a relationship between physical activity and mental wellbeing. However, the strength of the relationship is not consistent. Factors contributing to variation in the strength of association are not well understood and, therefore, it remains difficult to optimize physical activity to ensure the strongest possible relationship with mental health. Self-determination theory suggests that more autonomously motivated behaviors lead to better mental health outcomes, when compared to more controlled behaviors. Therefore, we examined whether autonomous and controlled motivation moderated the relationships between physical activity and affective wellbeing within two domains (i.e., leisure-time and active travel). METHODS: Between February and April 2014, adolescents (N = 1632, M age = 12.94 years, SD = 0.54, 55% male) wore an accelerometer across seven-days and completed self-report measures of leisure-time physical activity and active travel. They also completed two measures of motivation (towards leisure-time physical activity and active travel) and an affective wellbeing measure. RESULTS: Structural equation modeling revealed that greater self-reported leisure-time physical activity was associated with greater positive affect (ß = .29) and less negative affect (ß = -.19) and that motivation did not moderate these relationships. Self-reported active travel had no linear relationship with affective wellbeing, and motivation did not moderate these relationships. Accelerometer-measured leisure-time physical activity had no relationship with positive affect but, had a weak inverse association with negative affect (ß = -.09), and neither relationship was moderated by motivation. Accelerometer-measured active travel had no association with positive affect; however, autonomous motivation significantly moderated this association such that active travel had a positive association with positive affect when autonomous motivation was high (ß = .09), but a negative association when autonomous motivation was low (ß = -.07). Accelerometer-measured active travel had no association with negative affect. Despite some significant moderation effects, motivation did not consistently moderate the relationship between all physical activity variables (leisure-time and active travel, and self-report and accelerometer) and affective outcomes. CONCLUSIONS: Tailoring physical activity interventions and guidelines to prioritize leisure-time ahead of other life domains could benefit wellbeing. Promoting autonomous participation in active travel may also be associated with increased wellbeing among adolescents.

BCAP inhibits proliferation and differentiation of myeloid progenitors in the steady state and during demand situations.

B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) is a signaling adaptor expressed in mature hematopoietic cells, including monocytes and neutrophils. Here we investigated the role of BCAP in the homeostasis and development of these myeloid lineages. BCAP-/- mice had more bone marrow (BM) monocytes than wild-type (WT) mice, and in mixed WT:BCAP-/- BM chimeras, monocytes and neutrophils skewed toward BCAP-/- origin, showing a competitive advantage for BCAP-/- myeloid cells. BCAP was expressed in BM hematopoietic progenitors, including lineage-Sca-1+c-kit+ (LSK), common myeloid progenitor, and granulocyte/macrophage progenitor (GMP) cells. At the steady state, BCAP-/- GMP cells expressed more IRF8 and less C/EBPα than did WT GMP cells, which correlated with an increase in monocyte progenitors and a decrease in granulocyte progenitors among GMP cells. Strikingly, BCAP-/- progenitors proliferated and produced more myeloid cells of both neutrophil and monocyte/macrophage lineages than did WT progenitors in myeloid colony-forming unit assays, supporting a cell-intrinsic role of BCAP in inhibiting myeloid proliferation and differentiation. Consistent with these findings, during cyclophosphamide-induced myeloablation or specific monocyte depletion, BCAP-/- mice replenished circulating monocytes and neutrophils earlier than WT mice. During myeloid replenishment after cyclophosphamide-induced myeloablation, BCAP-/- mice had increased LSK proliferation and increased numbers of LSK and GMP cells compared with WT mice. Furthermore, BCAP-/- mice accumulated more monocytes and neutrophils in the spleen than did WT mice during Listeria monocytogenes infection. Together, these data identify BCAP as a novel inhibitor of myelopoiesis in the steady state and of emergency myelopoiesis during demand conditions.

Exploring identity in the 'figured worlds' of cancer care-giving and marriage in Australia.

Following changes in the structure and funding of the Australian medical system, patients have become 'consumers' or 'clients'. Family and friends have become 'carers' or 'caregivers', signifying their increased responsibilities as patients move from hospitals to communities. While policy makers embrace the term 'carer', some argue that the title is not widely recognised and has disempowering connotations. This paper examines spouses' reflections on the term 'carer' based on qualitative interviews with 32 Australians caring for a spouse with cancer from a study conducted between 2006 and 2009. Recruitment involved survey and snowball sampling. Following a grounded theory approach, data collection and analysis were performed simultaneously. Using Holland and colleagues' sociocultural 'identity as practice' theory and a thematic approach to analysis, findings depict identification with the 'spouse' and 'carer' label as relationally situated and dependent on meaningful interaction. Although others argue that the term 'carer' is a 'failure', these findings depict identification with the label as contextual, positional and enacted, not fixed. Furthermore, and of most significance to practitioners and policy makers, the title has value, providing carers with an opportunity to position themselves as entitled to inclusion and support, and providing health professionals with a potential indicator of a spouse's increased burden.

Association studies of Fcγ receptor polymorphisms with outcome in HER2+ breast cancer patients treated with trastuzumab in NCCTG (Alliance) Trial N9831.

Patients with HER2+ breast cancer treated with trastuzumab and chemotherapy have superior survival compared with patients treated with chemotherapy alone. Polymorphisms within FCGR2A and FCGR3A are associated with binding affinity of natural killer cells to the IgG1 portion of trastuzumab, and a polymorphism in FCGR2B (I232T) is associated with impaired regulatory activity. The association of these polymorphisms with clinical response among trastuzumab-treated patients is equivocal, with both positive and negative associations. We performed genotyping analysis on the FCGR3A V158F, FCGR2A R131H, and FCGR2B I232T polymorphisms in 1,325 patients from the N9831 clinical trial. Patients in arm A (N = 419) received chemotherapy only. Patients in arms B (N = 469) and C (N = 437) were treated with chemotherapy and trastuzumab (sequentially in arm B and concurrently in arm C). Using log-rank test and Cox proportional hazard models, we compared disease-free survival (DFS) among genotypic groups within pooled arms B/C. We found no differences in DFS between trastuzumab-treated patients who had the FCGR3A 158 V/V and/or FCGR2A 131 H/H high-affinity genotypes and patients without those genotypes. Furthermore, there was no significant interaction between FCGR3A and FCGR2A and treatment. However, there was a difference in DFS for FCGR2B I232T, with I/I patients deriving benefit from trastuzumab (P < 0.001), compared with the T carriers who did not (P = 0.81). The interaction between FCGR2B genotype and treatment was statistically significant (P = 0.03). Our analysis did not reveal an association between FcγR high-affinity genotypes and outcomes. However, it seems that the FCGR2B inhibitory gene may be predictive of adjuvant trastuzumab benefit.

Spondyloepiphyseal dysplasias and bilateral legg-calvé-perthes disease: diagnostic considerations for mucopolysaccharidoses.

Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, MIM 253200 ) is an autosomal recessive lysosomal storage disease (LSD) caused by decreased activity of arylsulfatase B (N-acetylgalactosamine 4-sulfatase) enzyme resulting in dermatan sulfate accumulation; mucopolysaccharidosis type IVA (MPS IVA, Morquio syndrome A, MIM 253000 ) by decreased activity of N-acetylgalactosamine 6-sulfatase enzyme resulting in accumulation of keratan sulfate. Clinical symptoms include coarse facial features, joint stiffness, hepatosplenomegaly, hip osteonecrosis, and dysostosis multiplex. MPS IVA symptoms are similar but with joint hypermobility.With suspicion of MPS disease, clinicians request urine studies for quantitative and qualitative glycosaminoglycans (GAGs). Diagnosis is confirmed by decreased enzyme activity in leukocytes or cultured skin fibroblasts. Further confirmation is obtained with identification of two mutations in the ARSB gene for MPS VI or mutations in the GALNS gene for MPS IVA.We report slowly progressing patients, one with MPS VI and two with MPS IVA, who presented with skeletal changes and hip findings resembling Legg-Calvé-Perthes disease or spondyloepiphyseal dysplasia and normal/near normal urine GAG levels. The urine analysis data presented suggest that present screening techniques for MPS are inadequate in milder patients and result in delayed or missed diagnoses. The patients presented in this paper emphasize the importance of enzymatic and molecular testing.

Is cancer care dependant on informal carers?

Over the past half century, medical care has become less institutionalised, more autonomous, equitable and less costly. This has led to a shift from hospital-based delivery to community care. This paper examines the experiences of Canberra-based carers following this shift using interview data from a longitudinal qualitative study of 32 informal carers of a spouse with cancer. Cancer patients experienced poorly coordinated care. When carers observed the effects of errors and miscommunication on patients, they felt compelled to coordinate patient care. Interview data suggest that informal carers of cancer patients are relied upon to manage patient care at home and in hospitals, but are not supported in undertaking this responsibility. This implies that carers should be a far more central focus in cancer care reform strategies.

Immunization of mice with the non-toxic HC50 domain of botulinum neurotoxin presented by rabies virus particles induces a strong immune response affording protection against high-dose botulinum neurotoxin challenge.

We previously showed that rabies virus (RABV) virions are excellent vehicles for antigen presentation. Here, a reverse genetic approach was applied to generate recombinant RABV that express a chimeric protein composed of the heavy chain carboxyterminal half (HC50) of botulinum neurotoxin type A (BoNT/A) and RABV glycoprotein (G). To promote surface expression and incorporation of HC50/A into RABV virions, the RABV glycoprotein (G) ER translocation sequence, various fragments of RABV ectodomain (ED) and cytoplasmic domain were fused to HC50/A. The HC50/A chimeric proteins were expressed on the surface of cells infected with all of the recombinant RABVs, however, the highest level of surface expression was detected by utilizing 30 amino acids of the RABV G ED (HV50/A-E30). Our results also indicated that this chimeric protein was effectively incorporated into RABV virions. Immunization of mice with inactivated RABV-HC50/A-E30 virions induced a robust anti-HC50/A IgG antibody response that efficiently neutralized circulating BoNT/A in vivo, and protected mice against 1000 fold the lethal dose of BoNT/A.

Managing hope, denial or temporal anomie? Informal cancer carers' accounts of spouses' cancer diagnoses.

Carers of cancer patients' emotional responses to cancer diagnoses have been a central focus within psycho-oncology. Some of this literature asserts that the maladaptive coping strategy denial is prevalent amongst carers. Using semi-structured, longitudinal interviews with 32 Australian Capital Territory carers of a spouse with cancer and an interactionist sociology of emotions framework to understanding their emotions, this study aimed to both contribute to the literature on cancer carers' coping strategies and provide a richer sociological depiction of carers' emotional reactions to a cancer diagnosis. The results raise questions about the value of singularly examining denial in cancer carers. Instead, these data suggest that carers use a range of coping strategies in the short-term and do emotion work to adapt to a challenged temporal orientation. The term temporal anomie is offered to describe carers' disrupted orientations in time and facilitate further discussion on the link between time and emotion work. Findings also show the importance of medical professionals' casting of the prognosis, from imminent death to certain future, to this temporal re-orientation and emotion work process. Instead of 'managing hope,' as much of the cancer communication literature describes it, findings suggest that physicians address cancer carers' and patients' temporal anomie. Future research might benefit from moving beyond individualistic conceptualisations of carers' emotions to include the cultural, temporal and interactionist influences.

Evidence that botulinum toxin receptors on epithelial cells and neuronal cells are not identical: implications for development of a non-neurotropic vaccine.

Botulinum toxin typically interacts with two types of cells to cause the disease botulism. The toxin initially interacts with epithelial cells in the gut or airway to undergo binding, transcytosis, and delivery to the general circulation. The toxin then interacts with peripheral cholinergic nerve endings to undergo binding, endocytosis, and delivery to the cytosol. The receptors for botulinum toxin on nerve cells have been identified, but receptors on epithelial cells remain unknown. The initial toxin binding site on nerve cells is a polysialoganglioside, so experiments were performed to determine whether polysialogangliosides are also receptors on epithelial cells. A series of single mutant and dimutant forms of the botulinum toxin type A binding domain (HC50) were cloned and expressed. One of these (dimutant HC50 A(W1266L,Y1267S)) was shown to have lost its ability to bind nerve cells (phrenic nerve-hemidiaphragm preparation), yet it retained its ability to bind and cross human epithelial monolayers (T-84 cells). In addition, the wild-type HC50 and the dimutant HC50 displayed the same ability to undergo binding and transcytosis (absorption) in a mouse model. The fact that the dimutant retained the ability to cross epithelial barriers but did not possess the ability to bind to nerve cells was exploited to create a mucosal vaccine that was non-neurotropic. The wild-type HC50 and non-neurotropic HC50 proved to be comparable in their abilities to: 1) evoke a circulating IgA and IgG response and 2) evoke protection against a substantial challenge dose of botulinum toxin.