SFX-01 in hospitalised patients with community-acquired pneumonia during the COVID-19 pandemic: a double-blind, randomised, placebo-controlled trial.

Introduction: Sulforaphane can induce the transcription factor, Nrf2, promoting antioxidant and anti-inflammatory responses. In this study, hospitalised patients with community-acquired pneumonia (CAP) were treated with stabilised synthetic sulforaphane (SFX-01) to evaluate impact on clinical status and inflammation. Methods: Double-blind, randomised, placebo-controlled trial of SFX-01 (300 mg oral capsule, once daily for 14 days) conducted in Dundee, UK, between November 2020 and May 2021. Patients had radiologically confirmed CAP and CURB-65 (confusion, urea >7 mmol·L-1, respiratory rate ≥30 breaths·min-1, blood pressure <90 mmHg (systolic) or ≤60 mmHg (diastolic), age ≥65 years) score ≥1. The primary outcome was the seven-point World Health Organization clinical status scale at day 15. Secondary outcomes included time to clinical improvement, length of stay and mortality. Effects on Nrf2 activity and inflammation were evaluated on days 1, 8 and 15 by measurement of 45 serum cytokines and mRNA sequencing of peripheral blood leukocytes. Results: The trial was terminated prematurely due to futility with 133 patients enrolled. 65 patients were randomised to SFX-01 treatment and 68 patients to placebo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was the cause of CAP in 103 (77%) cases. SFX-01 treatment did not improve clinical status at day 15 (adjusted OR 0.87, 95% CI 0.41-1.83; p=0.71), time to clinical improvement (adjusted hazard ratio (aHR) 1.02, 95% CI 0.70-1.49), length of stay (aHR 0.84, 95% CI 0.56-1.26) or 28-day mortality (aHR 1.45, 95% CI 0.67-3.16). The expression of Nrf2 targets and pro-inflammatory genes, including interleukin (IL)-6, IL-1ß and tumour necrosis factor-α, was not significantly changed by SFX-01 treatment. At days 8 and 15, respectively, 310 and 42 significant differentially expressed genes were identified between groups (false discovery rate adjusted p<0.05, log2FC >1). Conclusion: SFX-01 treatment did not improve clinical status or modulate key Nrf2 targets in patients with CAP primarily due to SARS-CoV-2 infection.

Extensive acute and sustained changes to neutrophil proteomes post-SARS-CoV-2 infection.

BACKGROUND: Neutrophils are important in the pathophysiology of coronavirus disease 2019 (COVID-19), but the molecular changes contributing to altered neutrophil phenotypes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We used quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes immediately following acute SARS-CoV-2 infection and during recovery. METHODS: Prospective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May to December 2020). Patients were enrolled within 96 h of admission, with longitudinal sampling up to 29 days. Control groups comprised non-COVID-19 acute lower respiratory tract infection (LRTI) and age-matched noninfected controls. Neutrophils were isolated from peripheral blood and analysed using mass spectrometry. COVID-19 severity and recovery were defined using the World Health Organization ordinal scale. RESULTS: Neutrophil proteomes from 84 COVID-19 patients were compared to those from 91 LRTI and 42 control participants. 5800 neutrophil proteins were identified, with >1700 proteins significantly changed in neutrophils from COVID-19 patients compared to noninfected controls. Neutrophils from COVID-19 patients initially all demonstrated a strong interferon signature, but this signature rapidly declined in patients with severe disease. Severe disease was associated with increased abundance of proteins involved in metabolism, immunosuppression and pattern recognition, while delayed recovery from COVID-19 was associated with decreased granule components and reduced abundance of metabolic proteins, chemokine and leukotriene receptors, integrins and inhibitory receptors. CONCLUSIONS: SARS-CoV-2 infection results in the sustained presence of circulating neutrophils with distinct proteomes suggesting altered metabolic and immunosuppressive profiles and altered capacities to respond to migratory signals and cues from other immune cells, pathogens or cytokines.

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial.

BACKGROUND: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. METHODS: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. FINDINGS: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. INTERPRETATION: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19. FUNDING: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.

Rural aquaculture as a sustainable alternative for forest conservation in the Monarch Butterfly Biosphere Reserve, Mexico.

Forest conservation plays a significant role in environmental sustainability. In Mexico only 8.48 million ha of forest are used for conservation of biodiversity. Payment for Environmental Services in the Monarch Butterfly Biosphere Reserve, one of the most important national protected areas, contributes to the conservation of these forests. In the Reserve, production of rainbow trout has been important for the rural communities who need to conserve the forest cover in order to maintain the hibernation cycle of the butterfly. Aquaculture is a highly productive activity for these protected areas, since it harnesses the existing water resources. In this study, changes from 1999 to 2012 in vegetation and land-use cover in the El Lindero basin within the Reserve were evaluated in order to determine the conservation status and to consider the feasibility of aquaculture as a means of sustainable development at community level. Evaluation involved stereoscopic interpretation of digital aerial photographs from 1999 to 2012 at 1:10,000 scale, comparative analysis by orthocorrected mosaics and restitution on the mosaics. Between 1999 and 2012, forested land recovered by 28.57 ha (2.70%) at the expense of non-forested areas, although forest degradation was 3.59%. Forest density increased by 16.87%. In the 46 ha outside the Reserve, deforestation spread by 0.26%, and land use change was 0.11%. The trend towards change in forest cover is closely related to conservation programmes, particularly payment for not extracting timber, reforestation campaigns and surveillance, whose effects have been exploited for the development of rural aquaculture; this is a new way to improve the socio-economic status of the population, to avoid logging and to achieve environmental sustainability in the Reserve.

Role of forest conservation in lessening land degradation in a temperate region: the Monarch Butterfly Biosphere Reserve, Mexico.

With international concern about the rates of deforestation worldwide, particular attention has been paid to Latin America. Forest conservation programmes in Mexico include Payment for Environmental Services (PES), a scheme that has been successfully introduced in the Monarch Butterfly Biosphere Reserve. To seek further evidence of the role of PES in lessening land degradation processes in a temperate region, the conservation state of the Cerro Prieto ejido within the Reserve was assessed by an analysis of changes in vegetation cover and land-use between 1971 and 2013. There were no changes in the total forest surface area, but the relative proportions of the different classes of cover density had changed. In 1971, closed and semi-closed forest occupied 247.81 ha and 5.38 ha, 82.33% and 1.79% of the total area of the ejido, respectively. By 2013, closed forest had decreased to 230.38 ha (76.54% of the ejido), and semi-closed cover was 17.23 ha (5.72% of the ejido), suggesting that some semi-closed forest had achieved closed status. The final balance between forest losses and recovery was: 29.63 ha were lost, whereas 13.72 ha were recovered. Losses were mainly linked to a sanitation harvest programme to control the bark beetle Scolytus mundus. Ecotourism associated with forest conservation in the Cerro Prieto ejido has been considered by inhabitants as a focal alternative for economic development. Consequently, it is essential to develop a well-planned and solidly structured approach based on social cohesion to foster a community-led sustainable development at local level.