Pneumonia is the leading infectious disease killer worldwide and commonly requires admission to critical care. Despite its prevalence, the underpinning biology of severe pneumonia remains incompletely understood. Here we perform multifaceted assessments of bronchoalveolar transcriptome, cytokines, microbiology, and clinical features to biologically characterise a cohort of patients with suspected severe pneumonia. Our data implicate three lung-restricted transcriptionally defined severe pneumonia endotypes (termed 'Pneumotypes' (Pn)). All three Pneumotypes have comparable clinical presentations and severity of respiratory failure but experience divergent outcomes. Pn1, the most common, is characterised by low alveolar cytokines, expanded tolerogenic macrophages and epithelial damage. Pn3 is characterised by immature neutrophil infiltration, IL-6-STAT3 activation and longer duration of mechanical ventilation. Pn2 displays the fastest resolution, exhibiting a balanced immune response and epithelial-endothelial repair signatures. We identify and validate mechanistically distinct phenotypes in the lungs of patients with suspected pneumonia and acute lung injury, implicating targets for personalised therapy.

Tumors foster an immunosuppressive microenvironment to evade the antitumor immune response. However, the influence of intratumoral immunosuppressive steroids on tumor-infiltrating natural killer (NK) cells and their implications for effective immunotherapy has remained largely unexplored. Here, we report that the functional enrichment of glucocorticoid cortisol signaling in the lung tumor microenvironment (TME) impairs NK cell anti-tumor cytotoxicity and exacerbates hypoxic stress. Cancer-associated fibroblasts (CAFs) and macrophages convert inactive cortisone to active cortisol, while T cells, fibroblasts, myeloid cells, macrophages, and cancer cells contribute to de novo steroid biosynthesis, collectively establishing a steroid-rich niche. Pharmacological inhibition of the glucocorticoid receptor (GR) in vivo alleviates cortisol-mediated immune suppression, resulting in reduced tumor growth and enhanced cytotoxicity of tumor-infiltrating NK cells. To overcome the cortisol-induced dysfunction of solid tumor targeting immunotherapy, we engineered chimeric antigen receptor (CAR) -NK cells specific to the Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (highly expressed in lung tumors) and rendered them cortisol-resistant by genetic deletion of the cortisol receptor gene NR3C1. In cortisol-rich niches, cortisol-resistant CAR-NK cells sustained antitumor cytotoxicity. Mechanistically, NR3C1 deletion relieved cortisol-mediated suppression of PI3K-AKT-NF-κB signaling, restored anti-tumor activity, and markedly reduced hypoxic stress. In lung metastasis models, cortisol-resistant CAR-NK cells achieved superior tumor control and significantly reduced tumor burden compared with conventional CAR-NK cells. Together, these findings identify local cortisol signaling as a critical barrier to solid tumor immunotherapy and establish cortisol-resistant CAR-NK cells as a promising strategy for targeting steroidogenic solid tumors, which can be combined with therapeutic glucocorticoids.

Background The complexity of delivering trauma care makes the assessment of its provision challenging. The identification of bellwether procedures has previously been successful in the evaluation of global surgical care; however, any equivalent in assessing trauma care is currently lacking. Through a Delphi process, we aimed to produce the bellwether procedures and processes for global trauma care.Methods A global Delphi process was undertaken with healthcare professionals and academics involved in trauma care from across the world. A list of potential procedures and processes was identified through literature review and expert opinion, along with subsequent additional options suggested by respondents. Three successive rounds were completed, with respondents rating the importance of each procedure or process to be undertaken at any hospital that cares for trauma patients using a five-point Likert scale.Results A total of 411 respondents from 78 countries completed the initial round of the Delphi process, with minimal attrition observed across rounds. Following three successive rounds of the Delphi and functional aggregation, nine bellwethers of global trauma care were determined, subdivided into three functional categories: ‘Resuscitation & Stabilisation’—(1) Advanced Airway Management, (2) Short-term C-spine Immobilisation, (3) Long Bone Immobilisation; ‘Diagnosis & Monitoring’—(4) Blood Gas Analysis, (5) Focused Assessment with Sonography in Trauma (FAST) Scanning, (6) Continuous Access to CT Imaging; ‘Optimisation & Intervention’—(7) Blood Transfusion, (8) Tube Thoracostomy, (9) Laparotomy and Splenectomy.Conclusion The Global Trauma Care Delphi study has produced nine metrics that provide pragmatic indicators for the overall assessment of trauma care capabilities at any healthcare setting worldwide. These bellwethers of global trauma care can enable hospitals, local managers and health ministries to identify institutions or regions that may require more in-depth assessment, allowing standards in the management of traumatic injuries to improve.

PURPOSE:Decisions regarding heparin formulation and thromboprophylaxis intensity are central to intensive care practice, yet the optimal strategy remains uncertain. We evaluated associations between anticoagulation strategies and three primary outcomes - life-threatening haemorrhage, thromboembolic events, and transfusion requirement - in a large international critically ill COVID-19 cohort. METHODS:Two analyses used variables pre-specified in the ESICM UNITE-COVID registry. First, outcomes were compared between unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) among patients receiving therapeutic anticoagulation for confirmed thromboembolism or with prophylactic intent. Second, outcomes were compared between standard and therapeutic-equivalent LMWH thromboprophylaxis with prophylactic intent. RESULTS:Among 3062 patients receiving therapeutic anticoagulation (811 UFH, 2251 LMWH), UFH was associated with higher rates of life-threatening haemorrhage (16.7% vs 7.7%; risk difference 9.0% [95% CI 5.8-12.3%]) and greater transfusion requirements (mean 4.2 vs 1.4 units; mean difference 2.79 [95% CI 2.11-3.47]). Among 1709 patients receiving therapeutic dose-equivalent anticoagulation with prophylactic intent, UFH was associated with more thromboembolic events (16.1% vs 9.7%; RD 6.4% [95% CI 1.5-11.3%]). Among 3555 patients receiving LMWH thromboprophylaxis, therapeutic-equivalent dosing was associated with fewer thromboembolic events (16.4% vs 22.0%; RD -5.6% [95% CI -9.2 to -1.7%]) without increased life-threatening haemorrhage (4.6% vs 5.8%; RD -1.2% [95% CI -3.5 to 1.1%]). CONCLUSIONS:During therapeutic anticoagulation, LMWH was associated with a more favourable observed safety profile than UFH, with lower rates of haemorrhage and transfusion requirements, and fewer thromboembolic events among patients treated with prophylactic intent. Higher-intensity LMWH thromboprophylaxis was associated with fewer thromboembolic events without increased haemorrhage; however, ICU mortality was higher in the therapeutic-equivalent group, a finding that may reflect residual confounding but warrants caution. These hypothesis-generating findings should be interpreted in the context of existing randomised trial evidence and evaluated prospectively.

BACKGROUND:The human lung hosts a highly specialised immune microenvironment responsible for defence, repair and responses to pathogens and environmental insults. Animal models insufficiently recapitulate human-specific immune pathways, limiting translational insight into both acute and chronic respiratory diseases. Advances in organoids, organ-on-chip technologies and biofabrication have enabled increasingly realistic in vitro lung models; however, many systems still lack immune components and the complexity required to capture dynamic host-immune interactions. CONTENT:This review outlines the existing impact of immune-competent lung models on clinical drug development and disease mechanistic studies, as well as the future potential and the technical challenges with integrating immune cells into in vitro lung models that need to be overcome to maximise clinical relevance. We discuss major bottlenecks and corresponding potential solutions, including immune cell viability and phenotype maintenance, microenvironmental compatibility, recruitment dynamics and the reproducibility-complexity trade-off. We further explore how cutting-edge biofabrication approaches, including tunable extracellular matrices, bioprinting and engineered microvascular networks, enable physiologically relevant interactions between immune and resident lung cell populations. CONCLUSION:Collectively, these advances pave the way for improved immune-competent lung models to accelerate therapeutic discovery and enhance model translational relevance.

Intensive care is under increasing pressure due to demographic changes, availability of new complex therapies, and workforce shortages, resulting in a relative reduction in resources. Technological advances such as digitalization, wearable sensors, and artificial intelligence promise to improve care delivery, enabling providers to offer equal or higher-quality care at lower costs. However, no healthcare system has yet demonstrated large-scale gains in the efficiency of intensive care delivery. A central requirement is the capacity to translate ideas and concepts into value, providing changes that make services, products, and optimal care more accessible and affordable to a larger population, generating value. Innovation should thus be acknowledged as a fourth principal pillar of intensive care, alongside clinical excellence, research, and teaching. This paper presents the opinion of a multidisciplinary expert panel, proposing a framework to support the generation, implementation, and evaluation of innovation in intensive care. We identify and examine key areas and applications where innovation is urgently needed, including workforce development, technology adoption, environmental sustainability, and the transformation of medical education. We also highlight barriers and concerns that must be addressed when implementing innovation in ICUs. We integrate these into a comprehensive framework illustrated through concrete examples. Finally, we argue that innovation should not be driven solely by academia or industry, but strategically led by healthcare professionals and patients’ representatives, grounded in ethics and data, interdisciplinary, and centered on patients’ and society’s needs. This framework offers a pathway for innovation, supporting a more inclusive, effective, and sustainable future for intensive care.

INTRODUCTION:Intensive care unit-acquired lower respiratory tract infections (ICU-LRTIs), including ventilator-associated pneumonia (VAP), ventilator-associated tracheobronchitis (VAT), and hospital-acquired pneumonia (vHAP) requiring invasive ventilation, remain among the most frequent and complex infections in critical care. Their management is challenged by diagnostic uncertainty, overlapping syndromes, and rising antimicrobial resistance. Despite advances in diagnostic and therapeutic tools, empirical broad-spectrum antibiotics remain the cornerstone of treatment, often started without microbiological confirmation. AREAS COVERED:This narrative review examines current approaches to ICU-LRTIs, with a focus on the growing role of bronchoscopy, molecular diagnostics, host biomarkers, and therapeutic drug monitoring (TDM). The need for harmonized definitions, such as ventilator-associated lower respiratory tract infection (VA-LRTI), is discussed to address diagnostic variability. The review also considers combined therapies, including nebulized antibiotics, novel antimicrobials targeting multidrug-resistant pathogens, and real-time TDM to optimize treatment in complex ICU cases. EXPERT OPINION:Management of VA-LRTIs is moving toward precision-guided care. Integrating bronchoscopy, molecular testing, and host-response profiling into routine practice can enable earlier, targeted therapy. Real-time TDM and local resistance surveillance should be standard to optimize antimicrobial use and prevent resistance. A shift from rigid syndromic classifications toward phenotype-driven management is needed to improve patient outcomes.

Clinical trials investigating the effect of systemic corticosteroids as an adjunctive therapy for severe community-acquired pneumonia (sCAP) requiring admission to the intensive care unit have produced heterogeneous results over recent decades. The most recent trials, despite being significantly larger than their predecessors, have displayed similarly heterogeneous results. This narrative review aims to explore the possible underlying reasons for this heterogeneity of treatment effect, providing detail for each of the proposed immune- and nonimmune-mediated mechanisms through which corticosteroids might offer therapeutic benefit for patients with severe pneumonia and providing an in-depth critical appraisal of the most recent large-scale multicentre randomised controlled trials, namely ESCAPe (2022), CAPE COD (2023) and REMAP-CAP (2025). We discuss the importance of recognising sCAP as a heterogeneous disease, in which local processes in the lung are not always reflected in systemic features, and the need for further characterisation of endotypes of the disease.

Purpose: Intensive care unit (ICU) strain is associated with increased mortality. Most strain metrics focus on simple measures such as bed occupancy or admissions. There is limited data mitigation strategies, such as procedure teams or staff well-being services on strain, or the impact of increased patient-to-nurse ratios and non-ICU trained nurses working in ICU. Methods: Using the multi-national UNITE-COVID study, collecting data from ICUs on their busiest day in two periods (2020 and 2021) of the COVID-19 pandemic, we evaluated metrics of strain (Bed occupancy, patient: nurse ratio, use of non-ICU staff and shortages of consumables) and potential mitigators (procedural support teams and staff well-being interventions). We examined how these related to outcomes (mortality, complications and length of stay). Results: In both epochs, ICUs experienced significant strain, with ICU bed expansion to 133% and 163% respectively, whilst patient-to-nurse ratios increased by 0.4 and 0.3. Consumable shortages were widespread in 2020. Mortality was inversely correlated with staff well-being interventions in both epochs. Complications were inversely correlated with procedure support teams, and positively correlated with staffing ratios. In regression models, pressure sores were reduced in presence of support teams (p=0.004) and increased with the increase in patients per nurse (p=0.05) whilst unplanned extubations were related to non-ICU trained staff working in ICU(p = 0.02). Conclusions: COVID-19 induced ICU strain had effects beyond mortality, including increases in complications. Staff pressure and lack of ICU training were related to specific complications, whilst support teams and well-being interventions were associated with improved outcomes. ### Competing Interest Statement ACM reports speaking fees from Biomerieux, Thermo-Fisher, Fischer and Paykel and Boston Scientific (paid to institution), he sits on the scientific advisory board of Cambridge Infection Diagnostics. MO has received research funding from Biomerieux and Baxter (paid to institution). JdW has consulted for Biomerieux, Menarini, MSD, Pfizer, Roche Diagnostics, ThermoFisher and Viatris (fees and honoraria paid to institution). PP reports speaking fees from Gilead, Mundipharma and advisory board fees from MSD, Biocodex. ### Funding Statement ACM is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1). JDW is supported by a Sr Clinical Research Grant from the Research Foundation Flanders (FWO, Ref. 1881020N). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study received approval from Ghent University Hospital Ethics committee, registration BC-07826 and appropriate approvals at each participating site in line with local regulations (ClinicalTrials.gov registration: [NCT04836065][1], retrospectively registered April 8th 2021). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04836065&atom=%2Fmedrxiv%2Fearly%2F2025%2F02%2F27%2F2025.02.27.25322947.atom

There are recognized diagnostic criteria for a first ventilator-associated pneumonia (VAP) episode, but not for recurrences. Many randomized clinical trials (RCTs) have used the recurrence of VAP as a criterion for efficacy evaluation. Still, the different definitions used in RCTs make it difficult to compare studies. We aimed to develop a consensual definition of VAP recurrences and of the various types of VAP recurrences. Thirty-six European experts constituting a multidisciplinary group of physicians (critical care, infectious diseases, microbiology) with special interest in the management of VAP were polled using the Delphi methodology. After the completion of four iterations of the DELPHI method, 94

Early antibiotic therapy for patients with severe infections is essential to improve outcomes. Conversely, use of overly broad antibiotic therapy for susceptible pathogens or unnecessary antibiotics in patients without bacterial infections is associated with adverse life-threatening events and superinfections. Antibiotics-induced changes in the human microbiota alter both immune and metabolic systems. Uncontrolled antibiotic use encourages emergence of antibiotic-resistant organisms. Around 50

Introduction Traumatic injuries are responsible for a huge amount of mortality, morbidity, and disability globally. Within global surgery, Bellwether procedures have previously been identified to measure the surgical proficiency of a hospital or a region, however traumatic injuries often have distinct epidemiological and demographic patterns, compared to routine surgical care. Using a focused set of procedures or processes to measure trauma performance could allow for improved trauma assessments and outcomes on a global scale. Methodology An international Delphi study will be conducted in attempt gain consensus on the optimal procedures and processes that can be used to assess the performance of trauma care within any region or hospital worldwide. Recognised guidelines for conducting the Delphi process will be followed, comprising of 3 separate rounds and participation from a public and patient involvement (PPI) group. Respondents will be identified through pre-existing collaborative networks and research partners, to ensure adequate global representation from across the trauma care pathway. The final Bellwether procedures will be those that have shown consensus in agreement and in stability throughout successive rounds Discussion This Delphi process aims to identify the optimal Bellwether metrics that could be used to assess trauma care worldwide. Using a focused set of procedures or processes to assess trauma performance globally will reduce complexity and improve ease of use compared to current methods. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement MF Bath is funded by the Royal College of Surgeons of England (RCS England) and the Engineering and Physical Sciences Research Council (EPSRC) Doctoral Training Partnership (DTP). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Study protocol only

Sepsis is a significant global health issue, with high morbidity, mortality, and economic burden. Its definition has evolved, with the latest Sepsis-3 criteria emphasizing life-threatening organ dysfunction due to a dysregulated host response. Endothelial dysfunction plays a critical role in sepsis pathogenesis, characterized by increased permeability and inflammatory responses. Human serum albumin, the most abundant protein in the bloodstream, is essential for maintaining oncotic pressure and endothelial integrity. This narrative review provides an overview of endothelial changes during sepsis and their impact on organ damage. We also explore the role of albumin administration in managing endothelial dysfunction in sepsis and discuss the available preclinical and clinical evidence.

Severe community-acquired pneumonia (sCAP) is associated with a significant health burden, both in the UK and globally, with intensive care support needed for many patients. The high morbidity and mortality associated with sCAP has led to the exploration of adjunctive therapies that may help reduce disease burden and improve clinical outcomes. One such proposed treatment is corticosteroids, aiming to moderate the disproportionate inflammation caused by sCAP. Despite several studies suggesting potential benefits, the use of corticosteroids in patients with sCAP remains contentious, with recent large trials producing conflicting results. These variations in trial outcomes have resulted in conflicting national and international guidelines. Such discrepancies align with findings from a recent national survey that indicated ongoing clinical uncertainty regarding the use of corticosteroids for sCAP in UK intensive care units. Several factors contribute to these conflicting outcomes, including patient population, the severity classification utilised, the type and duration of interventions provided, and, perhaps most importantly, the lack of pre-phenotyping to identify patients who may benefit most from the treatment. This narrative review aims to examine the recent literature, current guidelines, and evidence for using corticosteroids in sCAP, while exploring the candidate phenotypes of relevance in the design of clinical trials.

Intensive care unit (ICU) strain is associated with increased mortality. Most strain metrics focus on 'simple' measures such as bed occupancy or admission rates. There is limited data on mitigation strategies, such as procedure teams or staff well-being services on strain, or the impact of increased patient-to-nurse ratios and non-ICU trained nurses working in ICU. Using the multi-national UNITE-COVID study, collecting data from ICUs on their day of peak bed occupancy in two periods (2020 and 2021) of the COVID-19 pandemic, we evaluated metrics of strain (Bed occupancy, patient: nurse ratio, use of non-ICU staff and shortages of consumables) and potential mitigators (procedural support teams and staff well-being interventions). We examined how these related to outcomes (mortality, complications, length of stay). In both epochs, ICUs experienced significant strain, with ICU bed expansion to 133% and 163% respectively, whilst patient-to-nurse ratios increased by 0.4 and 0.3. Consumable shortages were widespread in 2020. Mortality was inversely correlated with staff well-being interventions in both epochs. Complications were inversely correlated with procedure support teams, and positively correlated with staffing ratios. In regression models, pressure sores were reduced in presence of support teams (p = 0.004) and increased with increasing patients per nurse (p = 0.05) whilst unplanned extubations were related to non-ICU trained staff working in ICU(p = 0.02). COVID-19 induced ICU strain had effects beyond mortality, including increases in complications. Staff pressure and lack of ICU training were related to specific complications, whilst support teams and well-being interventions were associated with improved outcomes.