Hypoxic pulmonary vasoconstriction increases systolic pulmonary artery pressure (sPAP) and may contribute to high-altitude pulmonary hypertension (HAPH). While supplemental oxygen therapy (SOT) lowers sPAP during acute hypoxic exposure, its haemodynamic effects in permanent high-altitude residents remain unclear. In particular, the relative contribution of fixed vascular remodelling to chronically elevated sPAP is uncertain.

In this open-label, non-randomised, sequential interventional trial, Kyrgyz highlanders living >2500 m with tricuspid regurgitation velocity >2.8 m/s underwent echocardiography under ambient air and after >15 min of high-dose SOT (FiO₂≈0.95, 10 L/min) at 3250 m.

48 participants (56% females, mean±SD age 53±12 years) completed the study per-protocol. SOT reduced sPAP from 45±11 to 31±5 mm Hg, cardiac output (CO) from 5.1±1.2 to 4.3±1.4 L/min and total pulmonary resistance (TPR) from 9.2±2.7 to 7.5±1.5 WU (all p<0.001). In an exploratory subanalysis, a larger sPAP decrease was associated with higher baseline sPAP and younger age.

High-dose SOT acutely lowers sPAP in high-altitude residents at risk for HAPH. The decrease in sPAP is driven by reductions in both CO and TPR. The decline in TPR indicates a largely reversible hypoxic-vasoconstrictor component, whereas the contribution of fixed vascular remodelling to elevated PAP appears minimal. These findings underscore the physiological potential of short-term high-dose oxygen to reduce right ventricular afterload and improve pulmonary haemodynamics in this high-altitude population at risk for HAPH.

NCT06489756.

Acute respiratory failure is common in the emergency department (ED), often requiring noninvasive respiratory support (NIRS). NIRS has become a cornerstone in the initial management of acute respiratory failure. Despite its growing use, significant variability in practice remains, and evidence-based guidance specific to the ED setting is limited. This article aims to provide emergency physicians with a practical, evidence-informed framework for initiating and managing NIRS in adults with acute respiratory failure, with a focus on initial settings, titration, monitoring for failure, and guidance on weaning and liberation.

Persistent hypoxemia after intubation is associated with high mortality and demands a systematic approach focused on the underlying pathophysiology. This article emphasizes developing a focused differential diagnosis that includes both mechanical and patient factors to guide management. The authors review key therapeutic strategies, including careful use of positive end expiratory pressure, positioning techniques, medications such as inhaled pulmonary vasodilators, sedation, and neuromuscular blockade, and, when conventional therapies fail, consideration of extracorporeal membrane oxygenation.

Respiratory tract infections (RTIs) remain a leading cause of global morbidity and mortality, and their clinical management is increasingly undermined by the biofilm mode of growth of major respiratory pathogens. Biofilm formation confers profound tolerance to conventional antibiotics through the extracellular polymeric substance (EPS) matrix, metabolic adaptations, and rapid acquisition of resistance, underscoring the need for new therapeutic strategies. Patents offer a valuable and timely insight into emerging technologies with translational potential. In this review, we analyse patents published between 2000 and 2025 that could be explored for the management of microbial biofilms related to respiratory infectious diseases. Using the WIPO Patentscope database, we identified 135 relevant patents and examined trends in patent activity, innovation classes, and proposed therapeutic modalities. These patents encompass a broad landscape of biological, chemical, and device-based strategies-including enzymes, peptides, nanoparticles, phages, probiotics, repurposed drugs, and engineered delivery systems-many of which demonstrate efficacy against biofilms formed by Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and other key respiratory pathogens. This 25-year patent analysis highlights a maturing innovation pipeline and reveals promising therapeutic directions for overcoming biofilm-associated recalcitrance in RTIs, offering a foundation for future drug development and clinical translation.

Although the bacterial microbiome in the respiratory tract is well-characterised, the fungal microbiome or mycobiome remains underexplored. We aimed to characterise the upper respiratory tract mycobiome within the general population, assess its variation across niches and in relation to host and environmental factors, and evaluate its role as a source community for the fungal pathogens Candida auris (also called Candidozyma auris), Candida albicans, and Aspergillus fumigatus.

In this cross-sectional population-based observational study, we characterised paired nasopharyngeal and oropharyngeal mycobiota from 108 participants in the Dutch population-based PIENTER-3 cohort using internal transcribed spacer-amplicon sequencing. Participants were recruited via municipal registers from four municipalities in the central Netherlands between Feb 1, 2016, and Oct 16, 2017. No clinical inclusion or exclusion criteria were applied. In addition, pan-Aspergillus and A fumigatus qPCR assays were performed on oropharynx samples. The primary outcome was to characterise niche-specific differences in the mycobiota.

We analysed samples from 108 participants (55 [51%] female and 53 [49%] male); the participant age ranged between 10 and 87 years (median 58; IQR 30-67). After quality-control filtering, 107 nasopharyngeal and 89 oropharyngeal samples were retained for analysis. Nasopharyngeal and oropharyngeal mycobiota differed in composition (p=0·0010) and diversity (p<0·0001), with greater heterogeneity in the oropharynx and higher diversity in the nasopharynx. We identified niche-specific factors influencing community structure; sampling season, degree of urbanisation, and livestock farm exposure shaped the nasopharyngeal mycobiota, particularly influencing the abundance of ubiquitous and plant-associated genera. In contrast, age, degree of urbanisation, and recent antibiotic use were key factors influencing the oropharyngeal mycobiome composition. Candida was highly prevalent in both niches, with the genus being more prevalent in the oropharynx (prevalence=85 [96%] of 89 samples) than in the nasopharynx (58 [54%] of 107 samples). Aspergillus was detected at low relative abundance in both niches and was more prevalent in the nasopharynx (49 [46%] of 107 samples) than in the oropharynx (27 [30%] of 89 samples). Although C albicans was frequently found, with its prevalence increasing with age, A fumigatus was not identified during internal transcribed spacer-amplicon sequencing or qPCR.

Our study identified niche-specific fungal communities, with their distinct influencing factors. Our findings also suggest that respiratory mycobiota might serve as a source community for potentially pathogenic fungi. Future studies should investigate which fungi represent commensals versus potential pathogens and elucidate the mechanisms underlying colonisation resistance and infection risk.

National Institute for Public Health and the Environment (RIVM), Netherlands Organization for Scientific Research, and Chief Scientist Office grant.

Pulmonary fibrosis (PF) is a progressive interstitial lung disease driven by excessive fibroblast activation and extracellular matrix (ECM) deposition, for which pirfenidone and nintedanib slow but do not halt disease progression. Extracellular vesicles (EVs)-lipid bilayer-enclosed nanoparticles that shuttle microRNAs (miRNAs), proteins, and lipids between cells-are increasingly recognized as important mediators and potential modulators of fibrotic remodeling. On the pathogenic side, epithelial- and immune-cell-derived EVs can deliver pro-fibrotic miRNAs (e.g., miR-494-3p) that regulate transforming growth factor beta (TGF-β)/Smad and Wnt/β-catenin signaling, promoting fibroblast-to-myofibroblast transition and ECM accumulation. Conversely, selected mesenchymal stem cell-derived EV (MSC-EV) preparations have demonstrated anti-fibrotic effects in preclinical models through modulation of TGF-β/Smad signaling, M2 macrophage polarization, mitochondrial function, and epithelial-mesenchymal transition; a phase I clinical study has provided initial safety evidence for nebulized administration, although therapeutic efficacy in PF has not yet been established. Beyond MSC-EVs, plant-derived and milk-derived EVs have emerged as potential delivery platforms, although their applications remain largely preclinical. Meanwhile, EVs isolated from plasma, bronchoalveolar lavage fluid, sputum, and urine carry disease-associated molecular signatures that may serve as candidate biomarkers for PF detection or monitoring, but require further clinical validation. This review synthesizes recent evidence on the dual roles of EVs in PF pathogenesis and therapy, evaluates their potential diagnostic utility, and discusses translational hurdles-including cargo standardization, targeted delivery, and scalable manufacturing-that must be overcome for clinical adoption.

The progression of tuberculosis (TB) to active disease is heavily influenced by innate immunity. Mycobacterium tuberculosis can alter host molecular pathways, compromising immune responses and facilitating infection. We aimed to determine molecular immunohistochemical markers in the lungs of mice infected with phylogenomically and pathobiologically different M. tuberculosis strains.

C57BL/6 male mice were infected with reference strain H37Rv (Euro-American lineage) and multidrug-resistant clinical strains 396 (highly lethal and hypervirulent subtype Beijing 14717-15) and 6691 (low-lethal and low-virulent subtype Beijing 1071-32). Lung tissues of the euthanized animals were obtained on days 14, 21, 60, and 120 after infection and were subjected to the histological and immunohistochemical analysis, including study of expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-12.

For strain 396, both disease progression and lung damage were associated with a highly reactive immune response and increased synthesis of iNOS and certain strain properties that may contribute to suppression of TNF-α production. In contrast, for strain 6691, a low reactivity of the immune response was detected, with statistically significantly lower values of the relative area of expression of iNOS and TNF-α at all time points.

The progression of the disease and damage of lung tissue in mice were associated with a highly reactive immune response, increased synthesis of iNOS, and strain properties that may reduce TNF-α production. iNOS and TNF-α can serve as molecular markers of the human immune response characterizing the differential virulence of these M. tuberculosis subtypes in a murine model.

Women working as informal food vendors in Kisumu faced precarious work conditions that worsened during the COVID-19 pandemic. Despite playing a vital role in urban household food security, they were excluded from policy decisions, which were largely confined to technical experts and national government officials.

Using the Intersectionality-Based Policy Analysis (IBPA) framework, this study examined the engagement of women informal food vendors and the disparities in COVID-19 control policies. Between July 10, 2024, and October 15, 2024, we conducted a qualitative study using key informant interviews (n = 20), in-depth interviews (n = 20), four focus group discussions (n = 40; 10 participants each), and a purposive review of four policy documents. Participants were recruited via purposive sampling in collaboration with Pamoja Community Based Organisation, and data were analyzed thematically guided by the IBPA principles.

The findings indicate that excluding women vendors from decision-making led to gender-insensitive policies that worsened existing inequalities by overlooking the vendors' diverse social identities. Furthermore, inconsistent policy implementation increased gender-based vulnerabilities, leaving these women exposed to harassment, extortion, and physical assault.

To prepare for future emergencies, governments must establish inclusive, gender-responsive policy frameworks that prioritize the perspectives of informal food vendors, thereby safeguarding sustainable urban food systems. Specifically, municipal, county, and national authorities should create consultative mechanisms to ensure women informal food vendors actively participate in decision-making processes. Such integration will foster gender-sensitive policy development and keep vendors' lived experiences central to urban food governance. Ultimately, this research demonstrates the value of applying an intersectional policy analysis framework to health research, advancing equity and social justice by strengthening the participation of marginalized groups in emergency response and regulatory planning.

Allergic rhinitis (AR) is a chronic inflammatory airway disease characterized by dysregulated type 2 immune responses and impaired mucosal immune regulation. Kynurenic acid (KYNA), an endogenous tryptophan metabolite with immunomodulatory properties, may influence inflammatory pathways, but its mechanisms in AR remain unclear. This study investigated KYNA in an ovalbumin (OVA)-induced rat model of AR and examined the role of aryl hydrocarbon receptor (AhR) signaling.

Rats were assigned to control, AR, vehicle, KYNA, desloratadine, and KYNA + AhR antagonist (CH223191) groups. Following OVA sensitization and challenge, behavioral responses, serum inflammatory markers, nasal AhR-associated proteins, regulatory cytokines, and histopathological changes in nasal and splenic tissues were evaluated.

OVA induced typical allergic responses, including increased sneezing and nasal scratching, elevated serum IgE, IL-4, and IL-6, and marked inflammatory changes in nasal and splenic tissues. KYNA significantly reduced behavioral symptoms, systemic inflammatory mediators, epithelial damage, and inflammatory infiltration, with systemic effects comparable to desloratadine but greater improvement in nasal scratching and splenic histopathology. KYNA restored nasal AhR and CYP1A1 expression and increased IL-10 and TGF-β, whereas CH223191 partially attenuated these effects, indicating involvement of AhR signaling. Desloratadine showed limited effects on local regulatory cytokines. Histopathological analysis confirmed improved nasal and splenic architecture following KYNA treatment.

In conclusion, KYNA attenuates experimental AR through systemic anti-inflammatory effects and restoration of mucosal immune regulation. AhR signaling contributes to these effects, particularly in CYP1A1 and cytokine regulation, while additional mechanisms may also be involved. These findings support KYNA as a potential immunometabolic modulator in allergic airway disease.

Gulf Cooperation Council countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and United Arab Emirates) have similar governance structures, economic profiles and health system organization, creating an opportunity for collective action on health. Similarly, these countries have the same challenges including ageing populations, climate and heat risks, immigration, service delivery and disease profiles. We argue for the need to shift from opinion-driven policy discourse to computer-based, decision-focused policy analysis that is participatory, aware of inherent uncertainties surrounding decisions and context-specific. Despite areas of excellence, modelling capacity in these countries is fragmented and underresourced and models are rarely used to guide decision-making. The coronavirus disease 2019 pandemic saw very few decision-oriented models tied to local data from Gulf Cooperation Council countries. Gulf Cooperation Council models rely on outside modellers, which limits both the relevance and ownership of the findings. The coming decade will bring challenges that demand a change in how evidence is generated and applied. A structured, regionally anchored policy-modelling system can help governments test reforms, prioritize investments and engage in scenario planning before crises force reactive measures. Our paper outlines pragmatic steps towards effective health policy modelling based on four supporting pillars: (i) a regional co-produced modelling and knowledge translation strategy tied to priority decisions; (ii) embedded capacity-building across ministries, public health institutes and universities; (iii) a viable modelling stack that allows transparency, speed and reproducibility; and (iv) explicit communication and evaluation of the uncertainty of models to reduce risks within the choices made.