A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study

Background The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107). Findings We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity. Interpretation We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care. Funding UK Research and Innovation and National Institute for Health Research

What Helps Oiled Wildlife Responders Care for Animals While Minimizing Stress and Compassion Fatigue

Oil spills are environmental disasters and their long-term impact is not just a concern for the environment and economy, but also for first responders' health and wellbeing. Wildlife, such as aquatic birds and certain marine mammals, are highly susceptible to physiological effects of oiling, and oiled wildlife responders are crucial to provide measures for their survival. The purpose of this research was to explore the experiences of oiled wildlife responders and what factors and conditions have helped or inhibited the responders to care-affected wildlife. This study collected responses (n = 50) from a survey of responders who attended either the New Zealand MV Rena or US Refugio pipeline oil spills. Study participants were mostly older (>40), highly educated females. We found there were significant differences in compassion satisfaction, resilience, burnout and overall satisfaction based on age, gender and role. While most responders have only attended limited numbers of oil spill incidents, they reported positive experiences and found it rewarding. Findings from responders indicated that to lessen stress and compassion fatigue during an incident, provision of training and support from professional organizations equips responders with knowledge and skills that can support their personal resilience to respond to disaster events

Influence of trawling on the behaviour and spatial distribution of Indo-Pacific bottlenose dolphins (Tursiops aduncus) in Moreton Bay, Australia

Sympatric communities of inshore Indo-Pacific bottlenose dolphins (Tursiops aduncus) have previously been identified within Moreton Bay, southeast Queensland, Australia. The two communities overlap in distribution, yet are almost completely socially segregated and forage in distinctly different ways. The correlation between this social segregation, the different foraging strategies, and a human activity (trawling) has previously been demonstrated. This paper investigates the possible effects of trawling on the behaviour and spatial distribution of these two communities. A geographical information system is used to determine the spatial use of each community. The behavioural budgets of both communities showed significantly higher levels of foraging behaviours than reported for most other bottlenose dolphin communities. The spatial use of both communities changed seasonally. These results provide further detail on how human activities may indirectly influence the behaviour and spatial use of free-ranging marine wildlife

GIS-based multi-criteria analysis of breeding habitats for recolonising species: New Zealand sea lions

The New Zealand sea lion (Phocarctos hookeri) is a threatened endemic species, with only three breeding colonies in the sub-Antarctic islands. Since 1993, there has been evidence for recolonisation of mainland New Zealand. Yet the coast that the sea lion has returned to only has fragmented and unevenly distributed potential habitats due to coastal urbanisation and development. Therefore, the need to identify and protect potential breeding habitats for recolonisation is a priority for management.A GIS-based multi-criteria analysis was used to identify potential suitable habitats for a 1600 km length of the NZ South Island coast based on distance to anthropogenic disturbance (urban areas, roads), distance to desirable environmental features (beaches, estuaries) and presence of suitable habitat/land access. From this model, we identified preliminary suitable habitat for breeding sites on the Otago Peninsula (east coast) and Catlins Coast (south). We independently detected some of the current dominant areas used by recolonising sea lions as well as identifying some promising new sites.We discuss the limitation of the results of this case study and the need for further data to be added to the model in the face of limited data availability. Overcoming this data limitation will meet an increasing need for a New Zealand-wide study for determining potential habitat for NZ sea lions. The results of such a study would identify areas to allow real-world management (protection or restoration) of the limited potential breeding sites for New Zealand sea lions. This new method could also be used for other recolonising species and encourage management of areas most likely to be recolonized by them

Trawling and bottlenose dolphins' social structure.

Human activities can affect the behaviour of mammals through the modification of habitats, changes in predation pressure or alterations in food distribution and availability. We analysed the association and ranging patterns of 242 individually identified bottlenose dolphins (Tursiops aduncus) in eastern Moreton Bay, Queensland, Australia, and distinguished two separate communities of dolphins. Unlike bottlenose dolphins elsewhere, the communities' core areas overlapped substantially. There was a correlation between the dolphins' responses to fishing activities and community membership-members of one community feed in association with trawlers and members of the other do not. Apart from feeding mode, the communities differed in habitat preference and group sizes. Inadvertent anthropogenic impacts on animals' societies are likely to be far more widespread than just this study and can increase conservation challenges. In this instance, managers need to consider the two communities' differing habitat requirements and their behavioural traditions in conservation planning

Dolphins restructure social system after reduction of commercial fisheries

Although human activities are known to affect the social behaviour of group-living animals, the resilience of animals' social structure to disturbance is poorly understood. In the 1990s, bottlenose dolphins, Tursiops aduncus, in Moreton Bay, Australia, formed two distinct social communities ('trawler' and 'nontrawler dolphins') based on foraging interactions (or lack thereof) with commercial prawn trawlers. Members of the two communities almost never associated, despite overlapping home ranges. Since then, changes to fisheries legislation have substantially reduced trawling in Moreton Bay. We used association analyses and social network metrics to compare patterns of sociality among bottlenose dolphins across two periods: 1997-1999 (during trawling) and 2008-2010 (post trawling). Over this decade, their social network became less differentiated and more compact (average geodesic distance between individuals decreased), with significantly more and stronger associations between individuals (mean and maximum half-weight indices increased). The previously described partitioning into two communities has disappeared, with former 'trawler' and 'nontrawler dolphins' now dispersed over the entire social network and associating with each other. This restructuring suggests that although fisheries can influence the social behaviour of bottlenose dolphins, their social structure represents a complex adaptive system that is resilient to disturbance