Core Function in Adults With Severe Asthma and Its Relationship With Breathing Symptoms.

BACKGROUND: People with asthma may have skeletal muscle dysfunction but data describing core function in severe asthma are limited. OBJECTIVE: To compare core function between people with severe asthma and healthy controls and to determine the difference between males and females. Furthermore, we aimed to investigate the association between core function and breathing symptoms. METHOD: Adults with a diagnosis of severe asthma and healthy controls undertook an assessment that included 3 core function tests: partial sit-up, Biering-Sorensen, and side bridge. Breathing symptoms were assessed by the modified Medical Research Council dyspnea scale, modified Borg scale, and Nijmegen questionnaire. RESULTS: People with severe asthma (n = 136) (38% male, age median [Q1-Q3] 59 y [45-68], body mass index 30 kg/m2 [26-37]) were compared with 66 people without respiratory disease (47% male, age 55 y [34-65], body mass index 25 kg/m2 [22-28]). There was no difference between groups in the partial sit-up (P = .09). However, participants with severe asthma performed worse with the Biering-Sorensen (P < .001), and the left and right side bridge test (P < .001 for both) than the healthy comparison group. Similar results were found when comparing males and females separately. Males with severe asthma had increased function compared with their female counterparts in the left side bridge test. Core function tests correlated with the breathing symptom measures, the modified Medical Research Council, modified Borg scale, and Nijmegen questionnaire (-0.51 > r > -0.19; P ≤ .03). CONCLUSIONS: Adults with severe asthma have worse core function than their control counterparts, independent of sex. Furthermore, as core function decreases, breathing symptoms increase.

Living With Asthma and Vocal Cord Dysfunction/Inducible Laryngeal Obstruction: "I Just Can't Get Air In".

BACKGROUND: Asthma and vocal cord dysfunction (VCD), also known as inducible laryngeal obstruction (ILO), may coexist, resulting in worse outcomes for patients. The experience of people with VCD/ILO and coexisting asthma is unknown. OBJECTIVE: We sought to determine whether coexistent VCD/ILO and asthma have deleterious impacts on quality of life. METHODS: We undertook a descriptive qualitative study using one-to-one semistructured interviews with 30 purposively recruited adult participants with a prior confirmed doctor asthma diagnosis and laryngoscopy-confirmed VCD/ILO. A thematic and content analysis was conducted to explore the data. RESULTS: Participants were mostly female (63%), mean ± SD age 63 ± 12 years. Four themes were identified: trapped voice, altered life, knowledge about VCD/ILO, and looking for solutions. Participants reported their voice being trapped in their throat or the voice being suddenly cut off when talking or singing. Self-reported VCD/ILO symptoms including throat tightness and breathlessness were highlighted by participants. The second theme described how patients struggle to communicate or tended to shorten conversations. Insufficient knowledge and existing confusion regarding whether asthma was causing the breathlessness was described in the third theme. Looking for solutions depicted participants' diagnostic journey and how they sought an explanation for the symptoms. CONCLUSIONS: People with asthma and coexisting VCD/ILO experience a substantial burden affecting the quality of life. These data describe the impact on patients with coexisting conditions and should be used to increase clinician awareness of the experience of VCD/ILO from patients' perspectives to support a personalized approach to care.

Cardiovascular outcomes of cancer patients in rural Australia.

Background: Cancer and heart disease are the two most common health conditions in the world, associated with high morbidity and mortality, with even worse outcomes in regional areas. Cardiovascular disease is the leading cause of death in cancer survivors. We aimed to evaluate the cardiovascular outcomes of patients receiving cancer treatment (CT) in a regional hospital. Methods: This was an observational retrospective cohort study in a single rural hospital over a ten-year period (17th February 2010 to 19th March 2019). Outcomes of all patients receiving CT during this period were compared to those who were admitted to the hospital without a cancer diagnosis. Results: 268 patients received CT during the study period. High rates of cardiovascular risk factors: hypertension (52.2%), smoking (54.9%), and dyslipidaemia (38.4%) were observed in the CT group. Patients who had CT were more likely to be readmitted with ACS (5.9% vs. 2.8% p = 0.005) and AF (8.2% vs. 4.5% p = 0.006) when compared to the general admission cohort. There was a statistically significant difference observed for all cause cardiac readmission, with a higher rate observed in the CT group (17.1% vs. 13.2% p = 0.042). Patients undergoing CT had a higher rate of mortality (49.5% vs. 10.2%, p ≤ 0.001) and shorter time (days) from first admission to death (401.06 vs. 994.91, p ≤ 0.001) when compared to the general admission cohort, acknowledging this reduction in survival may be driven at least in part by the cancer itself. Conclusion: There is an increased incidence of adverse cardiovascular outcomes, including higher readmission rate, higher mortality rate and shorter survival in people undergoing cancer treatment in rural environments. Rural cancer patients demonstrated a high burden of cardiovascular risk factors.

Associations of symptoms of anxiety and depression with health-status, asthma control, dyspnoea, dysfunction breathing and obesity in people with severe asthma.

BACKGROUND: Anxiety and depression are comorbidities of severe asthma. However, clinical characteristics associated with coexisting severe asthma and anxiety/depression are poorly understood. The study objective is to determine clinical characteristics associated with anxiety and depressive symptoms in severe asthma. METHODS: Severe asthma participants (N = 140) underwent a multidimensional assessment. Categorization of symptoms of anxiety and depression were based on HADS scale sub-scores and divided into four groups (< 8 on both subscales; ≥ 8 on one subscale; ≥ 8 on both subscales). Clinical characteristics were compared between subgroups. Multivariate logistic regression determined associations of clinical characteristics and anxiety and/or depressive symptoms in people with severe asthma. RESULTS: Participants were (mean ± SD) 59.3 ± 14.7 years old, and 62% female. There were 74 (53%) severe asthma participants without symptoms of anxiety/depression, 11 (7%) with symptoms of anxiety, 37 (26%) with symptoms of depression and 18 (13%) with symptoms of anxiety and depression. Quality of life impairment was greater in participants with symptoms of depression (4.4 ± 1.2) and combined symptoms of anxiety and depression (4.4 ± 1.1). Asthma control was worse in those with symptoms of depression (2.9 ± 1.1) and combined anxiety and depression (2.6 ± 1.0). In multivariate models, dysfunctional breathing was associated with symptoms of anxiety (OR = 1.24 [1.01, 1.53]). Dyspnoea was associated with symptoms of depression (OR = 1.90 [1.10, 3.25]). Dysfunctional breathing (OR 1.16 [1.04, 1.23]) and obesity (OR 1.17 [1.00, 1.35]) were associated with combined symptoms of anxiety and depression. CONCLUSION: People with severe asthma and anxiety and/or depressive symptoms have poorer QoL and asthma control. Dyspnoea, dysfunctional breathing and obesity are associated with these symptoms. These key clinical characteristics should be targeted in severe asthma management.

Multidisciplinary care in chronic airway diseases: the Newcastle model.

Chronic airway diseases including asthma and COPD are prevalent and high-burden conditions with the majority of patients successfully managed in the primary care setting. However, for some patients with more complex disease such as difficult-to-treat or severe asthma, or complex COPD, tertiary care is required. This review provides an overview of the successful tertiary care multidisciplinary respiratory service that operates in Newcastle, New South Wales, Australia, which has been integrated into the tertiary care outpatient clinics for almost three decades. The service is multifaceted in terms of the clinical care it provides; it includes an "Inpatient Service", "Asthma Management Service", "Difficult Airways Clinic", "Drug Administration Clinic", "Rapid Access Clinic" and "Pulmonary Rehabilitation", and has an integrated research programme. The core of the multidisciplinary approach to airway diseases is a person-centred model of care, the "Treatable Traits" approach. The staffing of this service comprises consultant physicians, respiratory advanced trainees, respiratory scientists, physiotherapists, speech pathologists, nurse specialists and a nurse consultant. Patients that present to this service undergo an initial assessment and clinical review by team members, synthesis of relevant data, and development of a diagnosis and management plan. Based on this clinical review, specific interventions are determined according to the traits identified. Over time the service has evolved to accommodate the increasing numbers of patients requiring access to the Difficult Airways Clinic assessment and therapies. This has been facilitated by partnering with the Centres of Excellence in Severe Asthma and Treatable Traits to develop educational and practice management tools.

Factors associated with 6-min walk distance in severe asthma: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Exercise capacity is associated with health-related quality of life and symptom control in severe asthma. Thus, interventions targeting exercise capacity are likely to be beneficial. However, clinical and biological factors impacting exercise capacity in severe asthma are sparsely investigated. We aimed to describe the association of selected clinical and biological factors with 6-min walk distance (6MWD) in adults with severe asthma and investigate the impact of sex on these outcomes. METHODS: A cross-sectional study in adults with severe asthma was conducted. Exercise capacity was measured by 6-min walk test, and association between 6MWD and predictors were evaluated using multiple linear regression. RESULTS: A total of 137 patients (females, 85; median age, 59 years) were recruited. Overall, asthma control (-15.2 m, 95% CI -22.6 to -7.7; p = 0.0001) and BMI (-3.2 m, 95% CI -5.1 to -1.3; p = 0.001) were significantly associated with exercise capacity (adjusted variance, adj. R2  = 0.425). In females, 5-item Asthma Control Questionnaire (ACQ-5; p = 0.005) and BMI (p < 0.001) were significantly associated with 6MWD (adj. R2  = 0.423). In males, a 0.5-point increase in ACQ-5 was associated with a decrease in 6MWD by 10.2 m (95% CI -22.8 to 2.4; p = 0.11), but no clinical nor biological factors reached statistical significance (adj. R2  = 0.393). CONCLUSION: Asthma symptoms and BMI were associated with exercise capacity in the overall population. Optimizing these factors may enhance the ability of patients to improve their exercise capacity and gain the associated positive health outcomes, but further studies are warranted.

Increasing physical activity in severe asthma: a systematic review and meta-analysis.

INTRODUCTION: Physical inactivity is common in asthma and is recognised as an important modifiable risk for poor clinical outcomes such as impaired asthma control and health-related quality of life (HRQoL). Despite evidence supporting the role of physical activity in reducing the risk of these outcomes, little is known about optimal interventions for increasing physical activity in those with severe disease. This systematic review and meta-analysis evaluates the effectiveness of interventions in increasing physical activity in severe asthma. METHODS: MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, Embase, PubMed, Informit, SPORTDiscus and Cochrane databases were searched up to September 2021 for physical activity-based intervention studies that assessed physical activity outcomes (e.g. steps per day, time spent undertaking physical activity) in adults with severe asthma. Data on asthma-related (e.g. asthma control) and health-related outcomes (e.g. HRQoL) were assessed as secondary outcomes. The revised Cochrane Risk of Bias tool was used to assess risk of bias. Random-effects meta-analyses synthesised data where possible. RESULTS: Four randomised controlled trials (all 12 weeks in duration) including 176 adults with moderate-to-severe asthma were included. An increase in physical activity was reported with a moderate-vigorous intensity aerobic and resistance training intervention (steps per day and time spent undertaking physical activity), and an unsupervised pedometer-based intervention (steps per day). Meta-analyses showed that physical activity interventions had an overall positive effect on steps per day (mean difference (MD) 1588, 95% CI 399-2778; p=0.009, I2=23), asthma control (MD -0.65, 95% CI -0.95--0.35; p<0.0001, I2=0%) and HRQoL (MD 0.56, 95% CI 0.10-1.01; p=0.02, I2=16%) compared to control. CONCLUSION: While there is some evidence supporting the effectiveness of interventions in improving physical activity in adults with severe asthma, higher-quality, large-scale studies of longer duration are needed to determine the optimal intervention.

Colonies of Acropora formosa with greater survival potential have reduced calcification rates.

Coral reefs are facing increasingly devasting impacts from ocean warming and acidification due to anthropogenic climate change. In addition to reducing greenhouse gas emissions, potential solutions have focused either on reducing light stress during heating, or on the potential for identifying or engineering "super corals". A large subset of these studies, however, have tended to focus primarily on the bleaching response of corals, and assume erroneously that corals that bleach earlier in a thermal event die first. Here, we explore how survival, observable bleaching, coral skeletal growth (as branch extension and densification), and coral tissue growth (protein and lipid concentrations) varies for conspecifics collected from distinctive reef zones at Heron Island on the Southern Great Barrier Reef. A reciprocal transplantation experiment was undertaken using the dominant reef building coral (Acropora formosa) between the highly variable reef flat and the less variable reef slope environments. Coral colonies originating from the reef flat had higher rates of survival and amassed greater protein densities but calcified at reduced rates compared to conspecifics originating from the reef slope. The energetics of both populations however potentially benefited from greater light intensity present in the shallows. Reef flat origin corals moved to the lower light intensity of the reef slope reduced protein density and calcification rates. For A. formosa, genetic differences, or long-term entrainment to a highly variable environment, appeared to promote coral survival at the expense of calcification. The response decouples coral survival from carbonate coral reef resilience, a response that was further exacerbated by reductions in irradiance. As we begin to discuss interventions necessitated by the CO2 that has already been released into the atmosphere, we need to prioritise our focus on the properties that maintain valuable carbonate ecosystems. Rapid and dense calcification by corals such as branching Acropora is essential to the ability of carbonate coral reefs to rebound following disturbance events and maintain 3D structure but may be the first property that is sacrificed to enable coral genet survival under stress.

Using a knowledge translation framework to identify health care professionals' perceived barriers and enablers for personalised severe asthma care.

BACKGROUND: Whilst multidimensional assessment enables the detection of treatable traits in severe asthma and has the potential to improve patient outcomes, healthcare disparities exist, and little is known about the factors influencing optimal management in severe asthma. This study aimed to explore perceived barriers, and enablers to implementing personalised care in severe asthma, from the healthcare professionals' perspective. METHODS: A descriptive, qualitative study involving a single focus group (n = 7) and semi-structured interviews (n = 33) with multidisciplinary healthcare professionals involved in severe asthma care was conducted. A hybrid thematic and content analysis was undertaken to identify themes, which were then deductively mapped to the Theoretical Domains Framework (TDF). RESULTS: Overall, three emergent themes were identified: (1) Barriers- (2) Enablers- to optimal management; (3) Desired model of care. Across all TDF domains, 6 constructs influenced development and implementation of optimal care: (1) belief about consequences, (2) environmental context and resources, (3) belief about capabilities, (4) social/professional role and identity, (5) goals and (6) knowledge. CONCLUSION: Implementation of personalised care in severe asthma is complex and non-linear. The use of a theory-based approach effectively demonstrated how a variety of behaviours could be targeted to optimise and promote personalised care in different clinical setting.

The needs and well-being of severe asthma and COPD carers: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Caring for people with severe asthma and chronic obstructive pulmonary disease (COPD) can impair the quality of life (QoL) of the carer. We aimed to describe the QoL and needs of severe asthma and COPD carers. METHODS: Carers of severe asthma (n = 89) and COPD (n = 48) completed an online cross-sectional survey assessing QoL and carer support needs using the Short Form Health Survey 12v2 (SF-12), the Hospital Anxiety and Depression Scale (HADS) and Carers Support Needs Assessment Tool (CSNAT) questionnaires. RESULTS: Carers of people with severe asthma and COPD were similar in age (mean ± SD 57.78 ± 14.09 vs. 56.93 ± 12.91) and gender (65% female vs. 66%); however, they differed in caring duration (proportion caring for >10 years: 65% vs. 33%, p < 0.002). QoL was impaired in both groups, but there were no significant differences between severe asthma and COPD carers in either of the SF-12 component scores. The HADS scores revealed no difference between groups. Compared to severe asthma carers, COPD carers had significantly greater needs for: 'having time for self' (33% vs. 13%, p = 0.006), 'equipment to help care for relative' (33% vs. 13%, p = 0.006), 'practical help in the home' (35% vs. 18%, p = 0.006) and 'getting a break from caring overnight' (21% vs. 6%, p = 0.023). CONCLUSION: QoL is impaired in carers of people with severe asthma to a similar degree of COPD carers and other debilitating diseases like cancer. These novel data highlight the support needs of severe asthma carers and identifies areas where tailored support is needed to reduce their substantial carer burden.

The Experience of Living with Severe Asthma, Depression and Anxiety: A Qualitative Art-Based Study.

PURPOSE: Severe asthma, depression and anxiety often co-exist and increase disease burden. Currently there are no published studies investigating severe asthma and psychological comorbidity using arts-based methodology. We aimed to (i) illustrate the individual experience of adults living with severe asthma, with and without symptoms of depression and/or anxiety and (ii) to explore common characteristics depicted in artworks between those groups. PATIENTS AND METHODS: A qualitative arts-based study was conducted. Adults with severe asthma were categorised into two groups according to Hospital Anxiety and Depression Scale scores (<8 on either subscale [SA-D/A] (N=15) or (≥8 on one or both subscales [SA+D/A] (N=15). Art thematic analysis was undertaken using a hybrid approach. The Common-Sense Model of Self-Regulation was used to examine frequencies in artworks. RESULTS: Participants with severe asthma alone and severe asthma with depression/anxiety were of older age (median 67 and 63 years respectively). There was greater asthma QoL impairment in participants with psychological comorbidity than without (4.7 ± 8.3 versus 5.8 ± 0.85, p=<0.01). Analysis of art works identified three themes: (1) "darkness" depicting misery, isolation and sadness; (2) "impacts" describing physical and social consequences; and (3) "resilience" illustrating acceptance and perseverance of living with all three conditions. CONCLUSION: Art-based research in severe asthma facilitates detailed exploration of intimate and individual experiences. Darkness, impacts and resilience are common themes emerging from artworks. Understanding these experiences may help guide assessment and treatment of psychological comorbidity in the clinic.

An integrated approach for characterizing immunogenic responses toward a bispecific antibody.

Bispecific antibodies (bsAbs) recognize and bind two different targets or two epitopes of the same antigen, making them an attractive diagnostic and treatment modality. Compared to the production of conventional bivalent monospecific antibodies, bsAbs require greater engineering and manufacturing. Therefore, bsAbs are more likely to differ from endogenous immunoglobulins and contain new epitopes that can increase immunogenic risk. Anti-A/B is a bsAb designed using a 'knobs-into-holes' (KIH) format. Anti-A/B exhibited an unexpectedly high immunogenicity in both preclinical and clinical studies, resulting in early termination of clinical development. Here, we used an integrated approach that combined in silico analysis, in vitro assays, and an in vivo study in non-human primates to characterize anti-A/B immunogenicity. Our findings indicated that the immunogenicity is associated with epitopes in the anti-B arm and not with mutations engineered through the KIH process. Our results showed the value of this integrated approach for performing immunogenicity risk assessment during clinical candidate selection to effectively mitigate risks during bsAb development.

All Hands-On Deck and All Decks on Hand: Surmounting Supply Chain Limitations During the COVID-19 Pandemic.

Testing during the COVID-19 pandemic has been crucial to public health surveillance and clinical care. Supply chain constraints-spanning limitations in testing kits, reagents, pipet tips, and swabs availability-have challenged the ability to scale COVID-19 testing. During the early months, sample collection kits shortages constrained planned testing expansions. In response, the University of Vermont Medical Center, University of Vermont College of Medicine, Vermont Department of Health Laboratory, Aspenti Health, and providers across Vermont including 16 area hospitals partnered to surmount these barriers. The primary objectives were to increase supply availability and manage utilization. Within the first month of Vermont's stay-at-home order, the University of Vermont Medical Center laboratory partnered with College of Medicine to create in-house collection kits, producing 5000 per week. University of Vermont Medical Center reassigned 4 phlebotomists, laboratory educators, and other laboratory staff, who had reduced workloads, to participate (requiring a total of 5.3-7.6 full-time equivalent (FTE) during the period of study). By August, automation at a local commercial laboratory produced 22,000 vials of media in one week (reducing the required personnel by 1.2 FTE). A multisite, cross-institutional approach was used to manage specimen collection kit utilization across Vermont. Hospital laboratory directors, managers, and providers agreed to order only as needed to avoid supply stockpiles and supported operational constraints through ongoing validations and kit assembly. Throughout this pandemic, Vermont has ranked highly in number of tests per million people, demonstrating the value of local collaboration to surmount obstacles during disease outbreaks and the importance of creative allocation of resources to address statewide needs.

What matters to people with severe asthma? Exploring add-on asthma medication and outcomes of importance.

There is an increasing number of new therapies for severe asthma; however, what outcomes people with severe asthma would like improved and what aspects they prioritise in new medications remain unknown. This study aimed to understand what outcomes are important to patients when prescribed new treatments and to determine the characteristics of importance to patients in their choice of asthma treatments. Participants with severe asthma (n=50) completed a cross-sectional survey that ranked 17 potential hypothetical outcomes of treatment using a seven-point Likert scale, as well as selecting their top five overall outcomes. Participants also completed hypothetical scenarios trading off medication characteristics for four hypothetical add-on asthma treatments. Participants (58% male), had a mean±sd age of 62.2±13.5 years. Their top three prioritised outcomes were: to improve overall quality of life (selected by 83% of people), reduce number and severity of asthma attacks (72.3%), and being able to participate in physical activity (59.6%) When trading off medication characteristics, the majority of patients with severe asthma chose the hypothetical medication with the best treatment efficacy (68%). However, a subgroup of patients prioritised the medication's side-effect profile and mode of delivery to select their preferred medication. People with severe asthma value improved quality of life as an important outcome of treatment. Shared decision-making discussions between clinicians and patients that centre around medication efficacy and side-effect profile can incorporate patient preferences for add-on therapy in severe asthma.

"It's like being on a roller coaster": the burden of caring for people with severe asthma.

INTRODUCTION: Family carers and significant others play a fundamental role in the well-being of people with severe asthma. This study aimed to investigate the challenges faced by family carers/significant others of people with severe asthma, to understand if there is an unmet need and to explore coping strategies. METHODS: Carers of people with severe asthma were invited to participate in a face-to-face or telephone interview. Semi-structured interviews were conducted until reaching data saturation of themes. The 20 interviews were recorded and transcribed, and analysis of data followed an inductive thematic approach. RESULTS: We report three overarching emergent themes: 1) "Caring role impacts", which centred around the negative and positive impacts of caring on carers' well-being; 2) "Unmet needs", which encapsulated the support needs participants desired and were categorised into unmet information, biopsychosocial needs and carers' involvement in decision-making; and 3) "Coping strategies", which were central to the range of tools and positive approaches in dealing with caring demands. DISCUSSION: Caring for someone with severe asthma can be burdensome and may negatively affect the physical and psychosocial health of the carer. Various coping strategies are used to manage the demands of these caring roles. Carers of people with severe asthma expressed a need for informational, biopsychosocial and involvement in care decision-making support. Tailored support services that are sensitive to their needs may improve their quality of life and encourage healthcare providers to value and acknowledge the important contribution that carers make.

The Patients' Experience of Severe Asthma Add-On Pharmacotherapies: A Qualitative Descriptive Study.

PURPOSE: Add-on therapies for severe asthma are continually emerging with proven efficacy in randomised controlled trials. To date, however, there are no qualitative studies exploring patients' experiences with these treatments. We aimed to understand the experience of patients who were treated with an add-on therapy for their severe asthma. PATIENTS AND METHODS: A qualitative descriptive study was conducted, participants were recruited from the respiratory clinics and databases of a tertiary referral hospital. Participants with treatment-refractory severe asthma (n=20) prescribed an add-on therapy for >4 months (75% mepolizumab; 25% omalizumab, and 25% macrolide) were recruited. Qualitative semi-structured interviews were conducted, with interviews thematically analysed. RESULTS: Participants' mean (SD) age was 59.5 (15.3) years, and 50% were male. Participants reported 4.5 (2.3) exacerbations in the past year. Asthma Control Questionnaire score was 2.0 (1.4). The monoclonal add-on therapies had been prescribed for a median (IQR) of 12.5 (7.0, 24.0) months. Experience was captured in four emergent themes: "Life is just easier" provided an overall message that the add-on therapy made the participants' life easier in terms of increasing participation, levelling out symptoms, providing more energy and reducing healthcare use. "Prednisone: A necessary evil" was discussed, particularly in terms of dose and dependence and damaging side effects. The theme "worry and hope for the future" referenced treatment non-response or cessation of effect which was discussed by some participants. Finally, "holistic care" was centred on the sentiment that the participant's asthma management and overall health were not related to one aspect or medication alone. CONCLUSION: Patients with severe asthma experience vast improvements in quality-of-life and life participation with add-on therapies, but there remains a significant burden related to oral corticosteroids and incomplete treatment responses. Addressing this residual burden is an important area for future research.

Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibody.

Systemic cytokine release and on-target/off-tumor toxicity to normal tissues are the main adverse effects limiting the clinical utility of T cell-redirecting therapies. This study was designed to determine how binding affinity for CD3 and tumor target HER2 impact the efficacy and nonclinical safety of anti-HER2/CD3 T cell-dependent antibodies (TDBs). Affinity was found to be a major determinant for the overall tolerability. Higher affinity for CD3 associated with rapidly elevated peripheral cytokine concentrations, weight loss in mice, and poor tolerability in cynomolgus monkeys. A TDB with lower CD3 affinity was better tolerated in cynomolgus monkeys compared with a higher CD3-affinity TDB. In contrast to tolerability, T cell binding affinity had only limited impact on in vitro and in vivo antitumor activity. High affinity for HER2 was critical for the tumor-killing activity of anti-HER2/CD3 TDBs, but higher HER2 affinity also associated with a more severe toxicity profile, including cytokine release and damage to HER2-expressing tissues. The tolerability of the anti-HER2/CD3 was improved by implementing a dose-fractionation strategy. Fine-tuning the affinities for both the tumor target and CD3 is likely a valuable strategy for achieving maximal therapeutic index of CD3 bispecific antibodies.

Severe Asthma Toolkit: an online resource for multidisciplinary health professionals-needs assessment, development process and user analytics with survey feedback.

OBJECTIVES: Severe asthma imposes a significant burden on individuals, families and the healthcare system. New treatment and management approaches are emerging as effective options for severe asthma. Translating new knowledge to multidisciplinary healthcare professionals is a priority. We developed 'The Severe Asthma Toolkit' (https://toolkit.severeasthma.org.au) to increase awareness of severe asthma, provide evidence-based resources and support decisionmaking by healthcare providers. SETTING: Roundtable discussions and a survey of Australians clinicians were conducted to determine clinician preferences, format and content for a severe asthma resource. PARTICIPANTS: A reference group from stakeholder and consumer bodies and severe asthma experts provided advice and feedback. A multidisciplinary team of international experts was engaged to develop content. Written content was based on up-to-date literature. Peer and editorial review were performed to finalise content and inform web design. Website design focused on user experience, navigation, engagement, interactivity and tailoring of content for a clinical audience. RESULTS: A web-based resource was developed. Roundtable discussions and a needs assessment survey identified the need for dedicated severe asthma management resources to support skills training. The end-product, which launched 26 March 2018, includes an overview of severe asthma, diagnosis and assessment, management, medications, comorbidities, living with severe asthma, establishing a clinic, paediatrics/adolescents and clinical resources. Analytics indicate access by users worldwide (32 169 users from 169 countries). User survey results (n=394) confirm access by the target audience (72% health professionals), who agreed the toolkit increased their knowledge (73%) and confidence in managing severe asthma (66%), and 75% are likely to use the resource in clinic. CONCLUSIONS: The Severe Asthma Toolkit is a unique, evidence-based internet resource to support healthcare professionals providing optimal care for people with severe asthma. It is a comprehensive, accessible and independent resource developed by leading severe asthma experts to improve clinician knowledge and skills in severe asthma management.

Targeting treatable traits in severe asthma: a randomised controlled trial.

RATIONALE: Treatable traits have been proposed as a new paradigm for airway disease management. OBJECTIVES: To characterise treatable traits in a severe asthma population and to determine the efficacy of targeting treatments to these treatable traits in severe asthma. METHODS: Participants (n=140) with severe asthma were recruited to a cross-sectional study and underwent a multidimensional assessment to characterise treatable traits. Eligible participants with severe asthma (n=55) participated in a 16-week parallel-group randomised controlled trial to determine the feasibility and efficacy of management targeted to predefined treatable traits, compared to usual care in a severe asthma clinic. The patient-reported outcome of health-related quality of life was the trial's primary end-point. MAIN RESULTS: Participants with severe asthma had a mean±sd of 10.44±3.03 traits per person, comprising 3.01±1.54 pulmonary and 4.85±1.86 extrapulmonary traits and 2.58±1.31 behavioural/risk factors. Individualised treatment that targeted the traits was feasible and led to significantly improved health-related quality of life (0.86 units, p<0.001) and asthma control (0.73, p=0.01). CONCLUSIONS: Multidimensional assessment enables detection of treatable traits and identifies a significant trait burden in severe asthma. Targeting these treatable traits using a personalised-medicine approach in severe asthma leads to improvements in health-related quality of life, asthma control and reduced primary care acute visits. Treatable traits may be an effective way to address the complexity of severe asthma.