Nebulised interferon beta-1a (SNG001) in the treatment of viral exacerbations of COPD.

BACKGROUND: Respiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-ß is naturally produced in response to viral infection, limiting replication. This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-ß1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance. METHODS: In Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation [i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids]). RESULTS: In Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001-placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments. CONCLUSIONS: Overall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study. TRIAL REGISTRATION: EU clinical trials register (2017-003679-75), 6 October 2017.

Recruitment rates and strategies in exercise trials in cancer survivorship: a systematic review.

PURPOSE: Despite clear evidence-based supporting a benefit to exercise on physical and psychological metrics in patients with cancer, recruitment to exercise trials amongst cancer survivors is suboptimal. We explore current recruitment rates, strategies, and common barriers to participation in exercise oncology trials in cancer survivorship. METHODS: A systematic review was conducted using a pre-defined search strategy in EMBASE, CINAHL, Medline, Cochrane Library, and Web of Science. The search was performed up to 28/02/2022. Screening of titles and abstracts, full-text review, and data extraction was completed in duplicate. RESULTS: Of the 3204 identified studies, 87 papers corresponding to 86 trials were included. Recruitment rates were highly variable with a median rate of 38% (range 0.52-100%). Trials recruiting prostate cancer patients only had the highest median recruitment rate (45.9%) vs trials recruiting colorectal cancer patients only which had the lowest (31.25%). Active recruitment strategies such as direct recruitment via a healthcare professional were associated with higher recruitment rates (rho = 0.201, p = 0.064). Common reasons for non-participation included lack of interest (46.51%, n (number of studies) = 40); distance and transport (45.3%, n = 39); and failure to contact (44.2%, n = 38). CONCLUSIONS: Recruitment of cancer survivors to exercise interventions is suboptimal with barriers being predominantly patient-oriented. This paper provides the benchmark for current recruitment rates to exercise oncology trials, providing data for trialists planning future trial design and implementation, optimise future recruitment strategies, and evaluate their own recruitment success against current practice. IMPLICATIONS FOR CANCER SURVIVORS: Enhanced recruitment to cancer survivorship exercise trials is necessary in facilitating the publication of definitive exercise guidelines, generalisable to varying cancer cohorts. PROSPERO REGISTRATION NUMBER: CRD42020185968.

A hospital to community exercise referral pathway: results of a pilot project.

BACKGROUND: People living with chronic disease should ideally engage with community-based exercise services following hospital-based rehabilitation. However, transition from hospital to community exercise settings is extremely challenging and strategies to support this transition are underdeveloped. AIMS: The aims of this study were to develop and explore the feasibility of a pilot exercise referral pathway between an acute hospital and community gyms for patients with chronic health conditions and to evaluate patient satisfaction with the exercise referral pathway. METHODS: A stakeholder-informed exercise referral pathway was developed and offered to patients following completion of a hospital-based exercise programme for a chronic health condition. The pathway was evaluated using a mixed-methods approach. Quantitative data examining participant engagement was used to examine feasibility. Quantitative survey data and qualitative data from semi-structured interviews examined satisfaction with the pathway. RESULTS: Forty-nine people living with chronic conditions (mean age 72 ± 7.8 years) participated (recruitment rate 59%). The average number of community gym visits over 4 months was 17.4 (range 0-51). Twenty-nine (78%) participants reported that they planned to continue their gym membership when the programme ended. Themed responses from participant interviews (n = 12) highlighted the benefits of a supported transition from hospital to gym membership and the need for more structured exercise support in community gyms. CONCLUSION: A structured exercise referral pathway to support exercise transition between hospital and community settings in populations with chronic health conditions appears feasible. Participants reported high levels of satisfaction with the referral pathway.

Outcomes and anticoagulation use for elderly patients that present with an acute hip fracture: multi-centre, retrospective analysis.

BACKGROUND: Hip fractures are a common problem and corrective surgery is recommended within 24 h. However, most peri-operative direct oral anticoagulant (DOAC) guidelines suggest a washout period of 48 h before major surgery. There are limited data on utility of drug levels. AIM: To investigate the effect of DOAC therapy on time to surgery and patient outcomes, and to explore the impact of different pre-operative protocols on surgical delay. METHODS: A multi-centre, retrospective analysis of all adult patients that presented with acute hip fracture at three tertiary hospitals in Perth, Western Australia, was performed. Data were collated from the West Australian hip fracture registry and electronic records. Time to theatre, DOAC levels, bleeding and transfusion rates were compared between sites. RESULTS: Of 1240 hip fracture patients, 146 (11.9%) were on anticoagulation, with more patients taking a DOAC than warfarin. The time to surgery was significantly longer for those on a DOAC compared with those on warfarin (P = 0.003). There was no difference in bleeding, transfusion requirement or 30-day mortality in patients taking a DOAC compared to those on warfarin. Fifty-eight (70.7%) patients had a DOAC level prior to surgery. Of 25 patients who had a level performed within 12 h of presentation, 13 (52%) had a result of ≤50 ng/mL. Outcomes were similar between sites. CONCLUSION: People on DOAC treatment had a significant delay before corrective surgery compared with those on warfarin. The frequent finding of early DOAC levels <50 ng/mL suggests this delay may be unnecessary in a significant proportion of patients.

Exercise and chronic health conditions in the community: A qualitative Study of Patients and Fitness instructors.

Further information is needed on how community exercise facilities can be effectively utilised to engage people living with chronic health conditions in exercise. The aim of this study was to identify the exercise barriers, facilitators and needs of patients with chronic disease in the community; and to provide recommendations to support the transition from hospital-based to community-based exercise. Using a qualitative approach, four focus groups were conducted with patients who had completed hospital-based exercise programmes (n = 11) and fitness instructors (n = 10). Data were audio recorded, member checked and transcribed verbatim for thematic analysis using NVivo. The side effects of chronic health conditions, the gym environment and a need for support when joining/attending a gym were perceived as barriers to exercising in the community. In contrast, the presence of supportive staff was perceived by patients as a facilitator to engaging in exercise in the community. A total of three themes emerged from participants views on exercise needs in the community; the referral and induction process in community gyms, fitness instructor training and experience and creating a supportive exercise environment. Themes informed eight key recommendations to support patients to exercise in the community, including supportive gym referral and induction processes for patients with chronic conditions, increased professional training for fitness instructors in the area of chronic disease management and exercise prescription, and exercise support at regular intervals for those with chronic conditions attending community gyms. This study found that there is potential for community gyms to play a key role in promoting health among people with chronic conditions. However, more can be done to foster an inclusive atmosphere in this space. Patients living with chronic conditions need information and advice on exercising in their communities. Community gyms require further support to ensure that facilities meet the exercise needs of people with chronic conditions.

Physical function in patients with resectable cancer of the pancreas and liver-a systematic review.

PURPOSE: Surgery is the only potentially curative treatment for pancreatic and liver cancer. However, even in high-volume centres, surgical resection is associated with significant morbidity with resultant physical decline. This systematic review explored physical function and its' implications in the management of resectable cancer of the pancreas and liver. METHODS: EMBASE, Medline OVID, CINAHL, Cochrane Library and Web of Science were searched up to June 2019 using a predefined search strategy. Screening of titles, abstracts, and full texts, data extraction, and risk of bias assessment was performed independently by two reviewers. A third reviewer resolved disagreements by consensus. RESULTS: Sixteen studies with a total of 1224 participants were included. Heterogeneity of the literature prevented a meta-analysis. Physical function across the pancreatic/liver cancer trajectory has been under investigated. The relationship between physical function and pancreatic/liver cancer resection outcome remains unclear, although anaerobic threshold appears the strongest predictor of postoperative outcomes. Conclusions regarding the impact of rehabilitative interventions on physical function were limited due to risk of bias concerns. CONCLUSIONS: High-quality evidence regarding the implications of physical function in resectable pancreatic and liver cancers is lacking. Well-designed trials are required to examine physical function across the pancreatic/liver cancer continuum and to measure the impact of rehabilitation on physical function. IMPLICATIONS FOR CANCER SURVIVORS: As survival rates for pancreatic and liver cancer slowly improve a greater understanding of the impact of these cancers and their treatments on physical function, and the potential impact of rehabilitative interventions for survivors is required.

The effects of repeated Toll-like receptors 2 and 4 stimulation in COPD alveolar macrophages.

Background: COPD is a progressive inflammatory airway disease characterized by increased numbers of alveolar macrophages in the lungs. Bacterial colonization of the lungs is a common feature in COPD and can promote inflammation through continual and repeated Toll-like receptor (TLR) stimulation. We have studied the response of COPD alveolar macrophages to repetitive stimulation with TLR2 and TLR4 ligands. We investigated the effect of sequential stimulation with different ligands to determine whether this results in tolerance or amplification of the immune response. Methods: We stimulated alveolar macrophages from COPD patients (n=9) and smokers (n=8) with the TLR4 agonist lipopolysaccharide (LPS) or the TLR2 agonist Pam3CSK4 for 24 hours before restimulating again for 24 hours. Cytokine protein release and gene expression were investigated. Results: Repetitive stimulation of COPD and smokers macrophages with LPS for both 24-hour periods caused a reduction in tumor necrosis factor α, CCL5, and IL-10 production compared to cells that were not exposed initially to LPS. IL-6 and CXCL8 production were not significantly altered following repetitive LPS stimulation. The same pattern was observed for repeated stimulation with Pam3CSK4. Using COPD macrophages, LPS followed by Pam3CSK4 stimulation increased the levels of all cytokines compared to media followed by Pam3CSK4. Conclusion: TLR tolerance in COPD alveolar macrophages occurs after repetitive stimulation with the same TLR ligand, but this only occurs for selected cytokines. CXCL8 production is not reduced after repetitive TLR stimulation with the same ligand; this may be an important mechanism for the increased CXCL8 levels that have been observed in COPD. We showed that TLR4 stimulation followed by TLR2 stimulation does not cause tolerance, but enhances cytokine production. This may be a relevant mechanism by which bacteria cause excessive inflammation in COPD patients.

The role of CRAC channel in asthma.

Asthma is increasing globally and current treatments only manage a proportion of patients. There is an urgent need to develop new therapies. Lymphocytes are thought to play a central role in the pathophysiology of asthma through the production of inflammatory mediators. This is thought to be via the transcription factor NFAT which in turn can be activated through Ca(2+) release-activated Ca(2+) (CRAC) channels. The aim of this work was to investigate the role of CRAC in clinical and pre-clinical models of allergic asthma. Initial data demonstrated that the NFAT pathway is increased in stimulated lymphocytes from asthmatics. To confirm a role for the channel we showed that a selective inhibitor, Synta 66, blocked mediator production from lymphocytes. Synta 66 inhibited CD2/3/28 induced IL-2, IL-7, IL-13 & IFNΥ in a concentration-dependent manner in healthy and severe asthma donors, with over 60% inhibition observed for all cytokines. NFAT pathway was also increased in a pre-clinical asthma model. In this model we have demonstrated that CRAC played a central role in the airway inflammation and late asthmatic response (LAR). In conclusion, our data provides evidence that suggests targeting CRAC channels could be of therapeutic benefit for asthma sufferers.

Site-Specific Immunomodulator: A Novel Treatment for Crohn's Disease.

We investigated the mechanism of action, safety, and efficacy of the Site-Specific Immunomodulator (SSI) QBECO, a novel immunotherapy for Crohn's disease (CD). Using human monocytic THP-1 cells, we demonstrate that SSI QBECO (derived from the common colon bacteria E. coli) activates macrophages to an M1 phenotype (associated with enhanced capacity to eliminate bacteria and activate innate immune responses). We assessed SSI QBECO in a compassionate use protocol of ten adult patients with active CD. Patients with moderate to severe clinical symptoms receiving conventional CD treatments and/or complementary therapies were included, except patients receiving anti-TNF medications. SSI QBECO was self-administered subcutaneously every second day, for a minimum of 2.5 months and a maximum of 11 months. All 10 patients reported improvement of symptoms while on the SSI QBECO treatment. Seven patients reported full resolution of clinical symptoms during a course of SSI QBECO of at least three months. Three patients have experienced ongoing sustained clinical remission after discontinuing all medications, including SSI treatment. The longest case of clinical remission is still ongoing (>4 years). No serious severe adverse clinical events were reported. Collectively, we conclude that treatment with the immunoactive SSI QBECO was well tolerated and effective for treatment of Crohn's disease in this case series.

The effects of corticosteroids on cytokine production from asthma lung lymphocytes.

BACKGROUND: Lymphocytes play a central role in the pathophysiology of asthma. Corticosteroids have a limited effect in severe asthma and we hypothesise that lymphocytes play a central role in corticosteroid insensitivity. We investigated the effects of corticosteroids on cytokine production from lung lymphocytes obtained from patients with moderate severe asthma (MSA) compared to mild asthma (MA) and healthy non-smokers (HNS). METHODS: Bronchoalveolar lavage (BAL) cells obtained by bronchoscopy from patients with MSA and MA (n = 11 and n = 14 respectively) and HNS (n = 7) were stimulated with CD2/3/28 beads to activate the lymphocytes, in the presence or absence of dexamethasone (0.01-1 µM). Supernatants were assayed for IL-2, IFNγ, IL-17, IL-13 and IL-10 production. RESULTS: Dexamethasone caused variable inhibition of cytokines; 1 µM inhibited IL-10 and IL-17 by 50% or lower, while inhibition > 50% was observed for IL-2, IL-13 and IFNγ. The effect of dexamethasone on IL-13 production was reduced in MSA. CONCLUSION: These findings suggest that the production of specific lymphocyte derived cytokines is poorly suppressed by corticosteroids in MSA, which may be responsible for persistent airway inflammation in these patients

CRAC channel inhibition produces greater anti-inflammatory effects than glucocorticoids in CD8 cells from COPD patients.

There are increased numbers of pulmonary CD8 lymphocytes in COPD (chronic obstructive pulmonary disease). CRAC (calcium release-activation calcium) channels play a central role in lymphocyte activation though the regulation of the transcription factor NFAT (nuclear factor of activated T-cells). We studied the expression of NFAT in lungs from COPD patients compared with controls, and evaluated the effects of CRAC channel inhibition compared with corticosteroids on NFAT activation and cytokine production in CD8 cells from COPD patients. The effects of the corticosteroid dexamethasone, the calcineurin inhibitor cyclosporin and the CRAC channel inhibitor Synta 66 were studied on cytokine production and NFAT activation using peripheral blood and isolated pulmonary CD8 cells. NFAT1 and CD8 co-expression in the lungs was compared in COPD patients and controls using combined immunohistochemistry and immunofluorescence. NFAT inhibition with either cyclosporin or Synta 66 resulted in significantly greater maximal inhibition of cytokines than dexamethasone in both peripheral blood and pulmonary CD8 cells [e.g. >95% inhibition of IFNγ (interferon γ) production from pulmonary CD8 cells using cyclosporin and Synta 66 compared with <50% using dexamethasone]. The absolute number of pulmonary CD8 cells co-expressing NFAT1 was significantly raised in lungs from COPD patients compared with controls, but the percentage of CD8 cells co-expressing NFAT1 was similar between COPD patients and controls (80.7% compared with 78.5% respectively, P=0.3). Inhibition of NFAT using the CRAC channel Synta 66 produces greater anti-inflammatory effects on CD8 cells from COPD patients than corticosteroids. NFAT is expressed at a high level in pulmonary CD8 cells in COPD.

Increased phosphorylated p38 mitogen-activated protein kinase in COPD lungs.

The p38 mitogen-activated protein kinase (MAPK) pathway is upregulated in chronic obstructive pulmonary disease (COPD). To date, dual labelling to identify cell-type-specific presence of phosphorylated (phospho-)p38 MAPK has not been carried out. Phospho-p38 MAPK was quantified in a variety of cell types in the lung tissue of 20 COPD patients, 12 smokers and 12 nonsmokers using immunohistochemistry. Paired blood and sputum neutrophils (from seven subjects with COPD), and CD8 and epithelial cells (from three subjects with COPD) were cultured with a p38 MAPK inhibitor. Supernatant tumour necrosis factor-α and CXCL8 levels were analysed by ELISA. Sputum and blood neutrophil cytospins were analysed for phospho-p38 MAPK. Phospho-p38 MAPK was increased in bronchial epithelial cells, macrophages and CD20+ and CD8+ lymphocytes in COPD lungs. Sputum and lung tissue neutrophils were devoid of phospho-p38 in all patient groups. The p38 MAPK inhibitor SB100 attenuated pro-inflammatory mediator release in COPD lung CD8 cells and airway epithelia, but there was no effect on COPD sputum neutrophils. Our data indicate cell-specific anti-inflammatory effects of p38 MAPK inhibition in the lung.