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Journal articlePates K, Shang Z, Jabbar R, et al., 2024,
The effects of COVID-19 on antifungal prescribing in the UK – lessons to learn
, Journal of Fungi, Vol: 10, ISSN: 2309-608XFungal infections are increasingly prevalent; however, antifungal stewardship attracts little funding or attention. Previous studies have shown that knowledge of guidelines and scientific evidence regarding antifungals is poor, leading to prescribing based on personal experiences and the inherent biases this entails. We carried out a retrospective study of inpatient antifungal usage at two major hospitals. We assessed the longitudinal trends in antifungal usage and the effect of COVID-19 on antifungal prescription, alongside levels of empirical and diagnostically targeted antifungal usage. Our results showed that the longitudinal patterns of total systemic antifungal usage within the trusts were similar to national prescribing trends; however, the composition of antifungals varied considerably, even when looking exclusively at the more homogenous group of COVID-19 patients. We showed a high level of empirical antifungal use in COVID-19 patients, with neither trust adhering to international recommendations and instead appearing to follow prior prescribing habits. This study highlights the significant challenges to optimise antifungal use with prescribing behaviour largely dictated by habit, a lack of adherence to guidelines, and high rates of empirical non-diagnostic-based prescribing. Further research and resources are required to understand the impact of antifungal stewardship on improving antifungal prescribing behaviours in this setting and the effects on outcome.
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Journal articleTiew PY, Leung JM, Mac Aogáin M, et al., 2024,
Residential exposure to Aspergillus spp. is associated with exacerbations in COPD.
, Eur Respir J, Vol: 64BACKGROUND: Sensitisation to Aspergillus fumigatus is linked to worse outcomes in patients with COPD; however, its prevalence and clinical implications in domestic (residential) settings remains unknown. METHODS: Individuals with COPD (n=43) recruited in Singapore had their residences prospectively sampled and assessed by shotgun metagenomic sequencing including indoor air, outdoor air and touch surfaces (a total of 126 specimens). The abundance of environmental A. fumigatus and the occurrence of A. fumigatus (Asp f) allergens in the environment were determined and immunological responses to A. fumigatus allergens determined in association with clinical outcomes including exacerbation frequency. Findings were validated in 12 individuals (31 specimens) with COPD in Vancouver, Canada, a climatically different region. RESULTS: 157 metagenomes from 43 homes were assessed. 11 and nine separate Aspergillus spp. were identified in Singapore and Vancouver, respectively. Despite climatic, temperature and humidity variation, A. fumigatus was detectable in the environment from both locations. The relative abundance of environmental A. fumigatus was significantly associated with exacerbation frequency in both Singapore (r=0.27, p=0.003) and Vancouver (r=0.49, p=0.01) and individuals with higher Asp f 3 sensitisation responses lived in homes with a greater abundance of environmental Asp f 3 allergens (p=0.037). Patients exposed and sensitised to Asp f 3 allergens demonstrated a higher rate of COPD exacerbations at 1-year follow-up (p=0.021). CONCLUSION: Environmental A. fumigatus exposure in the home environment including air and surfaces with resulting sensitisation carries pathogenic potential in individuals with COPD. Targeting domestic A. fumigatus abundance may reduce COPD exacerbations.
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Journal articleJaggi TK, Agarwal R, Tiew PY, et al., 2024,
Fungal lung disease.
, Eur Respir J, Vol: 64Fungal lung disease encompasses a wide spectrum of organisms and associated clinical conditions, presenting a significant global health challenge. The type and severity of disease are determined by underlying host immunity and infecting fungal strain. The most common group of diseases are associated with the filamentous fungus Aspergillus species and include allergic bronchopulmonary aspergillosis, sensitisation, aspergilloma and chronic and invasive pulmonary aspergillosis. Fungal lung disease remains epidemiologically heterogenous and is influenced by geography, environment and host comorbidities. Diagnostic modalities continue to evolve and now include novel molecular assays and biomarkers; however, persisting challenges include achieving rapid and accurate diagnosis, particularly in resource-limited settings, and in differentiating fungal infection from other pulmonary conditions. Treatment strategies for fungal lung diseases rely mainly on antifungal agents but the emergence of drug-resistant strains poses a substantial global threat and adds complexity to existing therapeutic challenges. Emerging antifungal agents and increasing insight into the lung mycobiome may offer fresh and personalised approaches to diagnosis and treatment. Innovative methodologies are required to mitigate drug resistance and the adverse effects of treatment. This state-of-the-art review describes the current landscape of fungal lung disease, highlighting key clinical insights, current challenges and emerging approaches for its diagnosis and treatment.
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Journal articleLong MB, Chotirmall SH, Shteinberg M, et al., 2024,
Rethinking bronchiectasis as an inflammatory disease.
, Lancet Respir Med, Vol: 12, Pages: 901-914Bronchiectasis is understood to be the result of a complex interaction between infection, impaired mucociliary clearance, inflammation, and lung damage. Current therapeutic approaches to bronchiectasis are heavily focused on management of infection along with enhancing mucus clearance. Long-term antibiotics have had limited success in clinical trials, suggesting a need to re-evaluate the concept of bronchiectasis as an infective disorder. We invoke the example of asthma, for which treatment paradigms shifted away from targeting smooth muscle constriction, towards permanently suppressing airway inflammation, reducing risk and ultimately inducing remission with precision anti-inflammatory treatments. In this Review, we argue that bronchiectasis is primarily a chronic inflammatory disease, requiring early identification of at-risk individuals, and we introduce a novel concept of disease activity with important implications for clinical practice and future research. A new generation of novel anti-inflammatory treatments are under development and repurposing of anti-inflammatory agents from other diseases could revolutionise patient care.
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Journal articleDomingo-Sabugo C, Willis-Owen SAG, Mandal A, et al., 2024,
Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid
, JOURNAL OF PATHOLOGY, Vol: 264, Pages: 332-343, ISSN: 0022-3417 -
Journal articleMolyneaux P, 2024,
The respiratory microbiome in patients with post-COVID-19 residual lung abnormalities resembles that of healthy individuals and is distinct from IPF
, ERJ Open Research, ISSN: 2312-0541 -
Journal articleSelvaraj M, Toghani A, Pai H, et al., 2024,
Activation of plant immunity through conversion of a helper NLR homodimer into a resistosome
, PLoS Biology, Vol: 22, ISSN: 1544-9173Nucleotide-binding domain and leucine-rich repeat (NLR) proteins can engage in complex interactions to detect pathogens and execute a robust immune response via downstream helper NLRs. However, the biochemical mechanisms of helper NLR activation by upstream sensor NLRs remain poorly understood. Here, we show that the coiled-coil helper NLR NRC2 from Nicotiana benthamiana accumulates in vivo as a homodimer that converts into a higher-order oligomer upon activation by its upstream virus disease resistance protein Rx. The cryo-EM structure of NbNRC2 in its resting state revealed intermolecular interactions that mediate homodimer formation and contribute to immune receptor autoinhibition. These dimerization interfaces have diverged between paralogous NRC proteins to insulate critical network nodes and enable redundant immune pathways, possibly to minimise undesired cross-activation and evade pathogen suppression of immunity. Our results expand the molecular mechanisms of NLR activation pointing to transition from homodimers to higher-order oligomeric resistosomes.
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Journal articlePark Y-K, Peng H, Hapeta P, et al., 2024,
Engineered cross-feeding creates inter- and intra-species synthetic yeast communities with enhanced bioproduction
, Nature Communications, Vol: 15, ISSN: 2041-1723Microorganisms can be engineered to sustainably produce a variety of products including fuels, pharmaceuticals, materials, and food. However, highly engineered strains often result in low production yield, due to undesired effects such as metabolic burden and the toxicity of intermediates. Drawing inspiration from natural ecosystems, the construction of a synthetic community with division of labor can offer advantages for bioproduction. This approach involves dividing specific tasks among community members, thereby enhancing the functionality of each member. In this study, we identify six pairs out of fifteen composed of six auxotrophs of Yarrowia lipolytica that spontaneously form robust syntrophic and synergistic communities. We characterize the stability and growth dynamics of these communities. Furthermore, we validate the existence of syntrophic interactions between two yeast species, Y. lipolytica and Saccharomyces cerevisiae, and find a strain combination, Δtrp2 and Δtrp4, forming a stable syntrophic community between two species. Subsequently, we introduce a 3-hydroxypropionic acid (3-HP) biosynthesis pathway into the syntrophic community by dividing the pathway among different strains. Our results demonstrate improved production of 3-HP in both intra- and interspecies communities compared to monocultures. Our results show the stable formation of synthetic syntrophic communities, and their potential in improving bioproduction processes.
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Journal articleMartin AK, Mercier O, Fritz AV, et al., 2024,
ISHLT consensus statement on the perioperative use of ECLS in lung transplantation: Part II: Intraoperative considerations.
, J Heart Lung TransplantThe use of extracorporeal life support (ECLS) throughout the perioperative phase of lung transplantation requires nuanced planning and execution by an integrated team of multidisciplinary experts. To date, no multidisciplinary consensus document has examined the perioperative considerations of how to best manage these patients. To address this challenge, this perioperative utilization of ECLS in lung transplantation consensus statement was approved for development by the International Society for Heart and Lung Transplantation Standards and Guidelines Committee. International experts across multiple disciplines, including cardiothoracic surgery, anesthesiology, critical care, pediatric pulmonology, adult pulmonology, pharmacy, psychology, physical therapy, nursing, and perfusion, were selected based on expertise and divided into subgroups examining the preoperative, intraoperative, and postoperative periods. Following a comprehensive literature review, each subgroup developed recommendations to examine via a structured Delphi methodology. Following 2 rounds of Delphi consensus, a total of 39 recommendations regarding intraoperative considerations for ECLS in lung transplantation met consensus criteria. These recommendations focus on the planning, implementation, management, and monitoring of ECLS throughout the entire intraoperative period.
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Journal articleShort C, Semple T, Abkir M, et al., 2024,
Silence of the lungs: comparing measures of slow and noncommunicating lung units from pulmonary function tests with computed tomography
, JOURNAL OF APPLIED PHYSIOLOGY, Vol: 137, Pages: 883-891, ISSN: 8750-7587
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