Assessment of Peripheral Airway Function following Chronic Allergen Challenge in a Sheep Model of Asthma

BACKGROUND: There is increasing evidence that the small airways contribute significantly to the pathophysiology of asthma. However, due to the difficulty in accessing distal lung regions in clinical settings, functional changes in the peripheral airways are often overlooked in studies of asthmatic patients. The aim of the current study was to characterize progressive changes in small airway function in sheep repeatedly challenged with house dust mite (HDM) allergen. METHODOLOGY/PRINCIPAL FINDINGS: Four spatially separate lung segments were utilized for HDM challenges. The right apical, right medial, right caudal and left caudal lung segments received 0, 8, 16 and 24 weekly challenges with HDM respectively. A wedged-bronchoscope technique was used to assess changes in peripheral resistance (R(p)) at rest, and in response to specific and non-specific stimuli throughout the trial. Allergen induced inflammatory cell infiltration into bronchoalveolar lavage and increases in R(p) in response to HDM and methacholine were localized to treated lung segments, with no changes observed in adjacent lung segments. The acute response to HDM was variable between sheep, and was significantly correlated to airway responsiveness to methacholine (r(s) = 0.095, P<0.01). There was no correlation between resting R(p) and the number of weeks of HDM exposure. Nor was there a correlation between the magnitude of early-phase airway response and the number of HDM-challenges. CONCLUSIONS: Our findings indicate that airway responses to allergic and non-allergic stimuli are localized to specific treated areas of the lung. Furthermore, while there was a decline in peripheral airway function with HDM exposure, this decrease was not correlated with the length of allergen challenge

Immune response to allergens in sheep sensitized to house dust mite

<p>Abstract</p> <p>Background</p> <p>House dust mite (HDM) allergens are a major cause of allergic asthma. Most studies using animal models of allergic asthma have used rodents sensitized with the 'un-natural' allergen ovalbumin. It has only recently been recognized that the use of animal models based on HDM provide a more relevant insight into the allergen-induced mechanisms that underpin human allergic disease. We have previously described a sheep model of human allergic asthma that uses <it>Dermatophagoides pteronyssinus </it>HDM. The present study extends our understanding of the immune effects of HDM and the allergens Der p 1 and Der p 2 in the sheep model of asthma.</p> <p>Methods</p> <p>Peripheral blood sera from non-sensitized (control) sheep and sheep sensitized to HDM was collected to determine immunoglobulin (Ig) reactivities to HDM, Der p 1 and Der p 2 by ELISA. Bronchoalveolar lavage (BAL) fluid collected following allergen challenge was also assessed for the presence of HDM-specific antibodies. To examine the cellular immune response to HDM allergens, T cell proliferation and cutaneous responses were assessed in sensitized and control sheep.</p> <p>Results</p> <p>Strong HDM- and Der p 1-specific IgE, IgG₁, IgG₂and IgA serum responses were observed in sensitized sheep, while detectable levels of HDM-specific IgG₁and IgA were seen in BAL fluid of allergen-challenged lungs. In contrast, minimal antibody reactivity was observed to Der p 2. Marked T cell proliferation and late phase cutaneous responses, accompanied by the recruitment of eosinophils, indicates the induction of a cellular and delayed-type hypersensitivity (DTH) type II response by HDM and Der p 1 allergen, but not Der p 2.</p> <p>Conclusion</p> <p>This work characterizes the humoral and cellular immune effects of HDM extract and its major constituent allergens in sheep sensitized to HDM. The effects of allergen in HDM-sensitized sheep were detectable both locally and systemically, and probably mediated via enzymatic and immune actions of the major HDM allergen Der p 1. This study extends our understanding of the actions of this important allergen relevant to human allergic asthma and its effects in sheep experimentally sensitized to HDM allergens.</p

Most patients reported positively or neutrally of having served as controls in the trials within cohorts design

Objectives: To evaluate patients’ experience of having served as controls without a notification at the time of randomization in the context of the trial within cohorts (TwiCs) design. Methods: Patients were asked for their opinion on having served as controls in TwiCs, before and after having been provided the trial results. Patients had provided broad consent to randomization at cohort entry and had served as controls in one of two TwiCs (an exercise program after breast cancer treatment or radiotherapy dose-escalation for rectal cancer). Results: Two to 6 years after cohort entry, 15% (n = 16) of all patients remembered having provided broad consent to randomization. Before disclosure of trial results, 47% (n = 52) of patients thought positively, 45% (n = 50) neutrally, and 2% (n = 2) negatively of having served as controls in one of the two trials. Seventeen percent (n = 18) of patients were positive, 65% (n = 71) neutral, and 11% (n = 12) negative about not having been notified when serving as controls. The survey results were comparable after disclosure of trial results. Conclusions: These results support the use of the TwiCs design with the staged-informed consent procedure. Keeping patients engaged and aware of the consents provided might further improve patients’ experience of serving as controls in TwiCs

Oncology patients were found to understand and accept the Trials within Cohorts design

Background and Objective: The Trials within Cohorts design aims to reduce recruitment difficulties and disappointment bias in pragmatic trials. On cohort enrollment, broad informed consent for randomization is asked, after which cohort participants can be randomized to interventions or serve as controls without further notification. We evaluated patients' recollection, understanding, and acceptance of broad consent in a clinical oncology setting. Methods: We surveyed 610 patients with cancer participating in ongoing TwiCs; 482 patients (79%) responded, of which 312 patients shortly after cohort enrollment, 108 patients after randomization to an intervention (12-18 months after cohort enrollment), and a random sample of 62 cohort participants who had not been selected for interventions (1-6 months after cohort enrollment). Results: Shortly after providing cohort consent, 76% of patients (238/312) adequately remembered whether they had given broad consent for randomization. Of patients randomly offered interventions, 76% (82/108) remembered giving broad consent for randomization; 41% (44/108) understood they were randomly selected, 44% (48/108) were not interested in selection procedures, and 10% (11/108) did not understand selection was random. Among patients not selected for interventions, 42% (26/62) understood selection was random; 89% felt neutral regarding the scenario of "not being selected for an intervention while your data were being used in comparison with patients receiving interventions,"10% felt reassured (6/62) and 2% scared/insecure (2/62). Conclusion: Patients adequately remember giving broad consent for randomization shortly after cohort enrollment and after being offered an intervention, but recollection is lower in those never selected for interventions. Patients are acceptant of serving as control without further notifications. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Stereotactic Radiotherapy Followed by Surgical Stabilization Within 24 h for Unstable Spinal Metastases; A Stage I/IIa Study According to the IDEAL Framework

Background: Routine treatment for unstable spinal metastases consists of surgical stabilization followed by external beam radiotherapy (EBRT) or stereotactic body radiotherapy (SBRT) after a minimum of 1–2 weeks to allow for initial wound healing. Although routine treatment, there are several downsides. First, radiotherapy induced pain relief is delayed by the time interval required for wound healing. Second, EBRT often requires multiple hospital visits and only 60% of the patients experience pain relief. Third, spinal implants cause imaging artifacts hindering SBRT treatment planning and delivery. Reversing the order of surgery and radiotherapy, with dose sparing of the surgical area by SBRT, could overcome these disadvantages and by eliminating the interval between the two treatments, recovery, and palliation may occur earlier.Design: The safety of SBRT followed by surgical stabilization within 24 h for the treatment of unstable spinal metastases was investigated. Safety was evaluated using the Common-Toxicity-Criteria-Adverse-Events-4.0, with the occurrence of wound complications within 90-days being the primary concern.Results: Between June-2015 and January-2017, 13 patients underwent SBRT followed by surgical stabilization for unstable spinal metastases. The median time between SBRT and surgery was 17-h (IQR 5–19). None of the patients experienced wound complications. Improvements in pain and quality of life were observed over time for all patients.Conclusion: SBRT followed by surgical stabilization within 24 h for the treatment of unstable spinal metastases is safe. Palliation may be experienced earlier and with both treatments being performed in one hospital admission the treatment burden decreases

Appropriateness of the 30-day expected mortality metric in palliative radiation treatment: a narrative review

BACKGROUND AND OBJECTIVE The 30-day expected mortality rate is frequently used as a metric to determine which patients benefit from palliative radiation treatment (RT). We conducted a narrative review to examine whether its use as a metric might be appropriate for patient selection. METHODS A literature review was conducted to identify relevant studies that highlight the benefits of palliative RT in timely symptom management among patients with a poor performance status, the accuracy of predicting survival near the end of life and ways to speed up the process of RT administration through rapid response clinics. KEY CONTENT AND FINDINGS Several trials have demonstrated substantial response rates for pain and/or bleeding by four weeks and sometimes within the first two weeks after RT. Models of patient survival have limited accuracy, particularly for predicting whether patients will die within the next 30 days. Dedicated Rapid Access Palliative RT (RAPRT) clinics, in which patients are assessed, simulated and treated on the same day, reduce the number of patient visits to the radiation oncology department and hence the burden on the patient as well as costs. CONCLUSIONS Single-fraction palliative RT should be offered to eligible patients if they are able to attend treatment and could potentially benefit from symptom palliation, irrespective of predicted life expectancy. We discourage the routine use of the 30-day mortality as the only metric to decide whether to offer RT. More common implementation of RAPRT clinics could result in a significant benefit for patients of all life expectancies, but particularly those having short ones

The ethics of ‘Trials within Cohorts’ (TwiCs): 2nd international symposium - London, UK. 7-8 November 2016

On 7-8 th November 2016, 60 people with an interest in the ‘ Trials within Cohorts ’ (TwiCs) approach for randomised controlled trial design met in London. The purpose of this 2 nd TwiCs international symposium was to share perspectives and experiences on ethical aspects of the TwiCs design, discuss how TwiCs relate to the current ethical frame- work, provide a forum in which to discuss and debate ethical issues and identify future directions for conceptual and empirical research. The symposium was supported by the Wellcome Trust and the NIHR CLAHRC Yorkshire and Humber and organised by members of the TwiCs network led by Clare Relton and attended by people from the UK, the Netherlands, Norway, Canada and USA. The two-day sympo- sium enabled an international group to meet and share experiences of the TwiCs design (also known as the ‘ cohort multiple RCT design ’ ), and to discuss plans for future research. Over the two days, invited plenary talks were interspersed by discussions, posters and mini pre- sentations from bioethicists, triallists and health research regulators. Key findings of the symposium were: (1) It is possible to make a compelling case to ethics committees that TwiCs designs are ap- propriate and ethical; (2) The importance of wider considerations around the ethics of inefficient trial designs; and (3) some questions about the ethical requirements for content and timing of informed consent for a study using the TwiCs design need to be decided on a case-by-case basis

Increased Mast Cell Density and Airway Responses to Allergic and Non-Allergic Stimuli in a Sheep Model of Chronic Asthma

BACKGROUND: Increased mast cell (MC) density and changes in their distribution in airway tissues is thought to contribute significantly to the pathophysiology of asthma. However, the time sequence for these changes and how they impact small airway function in asthma is not fully understood. The aim of the current study was to characterise temporal changes in airway MC density and correlate these changes with functional airway responses in sheep chronically challenged with house dust mite (HDM) allergen. METHODOLOGY/PRINCIPAL FINDINGS: MC density was examined on lung tissue from four spatially separate lung segments of allergic sheep which received weekly challenges with HDM allergen for 0, 8, 16 or 24 weeks. Lung tissue was collected from each segment 7 days following the final challenge. The density of tryptase-positive and chymase-positive MCs (MC(T) and MC(TC) respectively) was assessed by morphometric analysis of airway sections immunohistochemically stained with antibodies against MC tryptase and chymase. MC(T) and MC(TC) density was increased in small bronchi following 24 weeks of HDM challenges compared with controls (P<0.05). The MC(TC)/MC(T) ratio was significantly increased in HDM challenged sheep compared to controls (P<0.05). MC(T) and MC(TC) density was inversely correlated with allergen-induced increases in peripheral airway resistance after 24 weeks of allergen exposure (P<0.05). MC(T) density was also negatively correlated with airway responsiveness after 24 challenges (P<0.01). CONCLUSIONS: MC(T) and MC(TC) density in the small airways correlates with better lung function in this sheep model of chronic asthma. Whether this finding indicates that under some conditions mast cells have protective activities in asthma, or that other explanations are to be considered requires further investigation