Pulmonary artery pseudoaneurysm (PAP) is a rare but potentially fatal entity caused by a variety of underlying conditions. They may be congenital in origin or occur due to infective complications or occasionally secondary to pulmonary arterial hypertension. Among infective processes, tuberculosis and bacterial infections are the most common causative agents. There are few isolated reports of angio-invasive mucormycosis causing PAP; many of them were detected postmortem. Diagnosis of specific aetiology is often overlooked due to lack of clinical suspicion, as a result of incomplete investigations or due to inappropriate imaging. This report presents a case of pulmonary mucormycosis complicated by PAP in a patient with clinically unsuspected, uncontrolled diabetes. We highlight how the combination of heightened clinical suspicion, appropriate imaging and timely intervention helped us to treat a potentially fatal complication in our patient.

Pulmonary non-tuberculous mycobacterial (NTM) disease is a respiratory infection with an increasing incidence worldwide, including Japan. Host factors may also be involved in the establishment of pulmonary NTM disease. Cystic fibrosis transmembrane conductance regulator (CFTR) variants are associated with pulmonary NTM disease and bronchiectasis. However, data on CFTR variants in the Japanese population remain limited.

We aimed to determine the frequency of CFTR variants and the impact on the clinical features of pulmonary NTM disease and bronchiectasis in the Japanese population.

We analysed 458 patients with either pulmonary NTM disease, non-cystic fibrosis bronchiectasis or both at Keio University Hospital from February 2016 to March 2019. CFTR variants were identified using exome sequencing, Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). These variants were determined to be deleterious using CFTR2 and in silico tools. Clinical characteristics of patients with and without CFTR variants were compared in a 1:8 age-matched and sex-matched ratio. Additionally, exome sequencing was performed for the family of a patient with a family history of pulmonary NTM disease.

Deleterious CFTR variants were identified in 16 patients (3.5%). One variant was identified by MLPA, and 15 by Sanger sequencing. All patients harboured a CFTR variant in one allele. Compared with matched controls, these patients had lower sputum culture conversion rates and higher rates of macrolide resistance. In one family cluster, members with pulmonary NTM disease were found to carry the same CFTR variant.

We defined the frequency and clinical characteristics of CFTR variants among the Japanese population with either pulmonary NTM disease, non-cystic fibrosis bronchiectasis or both and found that patients with CFTR variants may be refractory to pulmonary Mycobacterium avium complex disease. Further comprehensive research is needed to assess the impact of CFTR variants on pulmonary NTM disease and bronchiectasis in non-European populations.

Ceftazidime/avibactam (CZA) resistance (CZAr) poses critical challenges for the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. The early identification of high-risk populations is essential for controlling nosocomial transmission and guiding empirical therapy. This study aimed to systematically focus on the correlation between the clinical characteristics of patients and the microbial features of CZArCRKP.

We conducted a retrospective cohort study (January 2020-May 2023) of 97 patients with CRKP infection. Antimicrobial susceptibility testing and whole-genome sequencing (WGS) were used to analyze resistance phenotype-genotype correlations. Survival outcomes were evaluated using Kaplan-Meier analysis.

CZArCRKP primarily caused lower respiratory (72.16 %) and urinary tract (16.49 %) infections, predominantly affecting elderly patients with comorbidities (81.4 %) or undergoing invasive procedures (63.9 %). Chronic renal failure combined with platelet counts > 149× 10⁹/L post-infection strongly predicted patients with CZArCRKP in pulmonary infections. NDM-1 gene carriage and OmpK36 mutations were associated with CZA resistance. CZA-treated patients demonstrated lower 14-day mortality rates.

We established the first integrated host-pathogen risk model for CZArCRKP and identified chronic renal failure and platelet count as key clinical predictors. NDM-1/OmpK36 mutations represents a clear mechanism of resistance. CZA use may improve the survival of selected patients with CRKP. These findings advance the surveillance and therapeutic strategies for multidrug-resistant infections.

The Hedgehog pathway may be involved in chronic obstructive pulmonary disease (COPD). Its inhibitor, Vismodegib, has therapeutic potential, but the underlying mechanisms require further investigation. A COPD mouse model was established using lipopolysaccharide (LPS) and cigarette smoke exposure, with concurrent Vismodegib intervention. Assessments included histopathology, pulmonary function, inflammatory cytokines, neutrophil extracellular traps (NETs) markers, macrophage polarization, and integrated transcriptomic and gut microbiota (16S rRNA) analysis. The results show that Vismodegib alleviated lung injury and fibrosis, regulated the respiratory rate, reduced the levels of pro-inflammatory cytokines such as interleukin (IL)-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α), promoted a phenotypic shift from M1 to M2 macrophage polarization, and suppressed NETs formation, as demonstrated by decreased levels of neutrophil elastase (NE), citrullinated histone H3 (Cit-H3), myeloperoxidase (MPO), and Cit-H3⁺Ly6G⁺ cells. Multi-omics analysis revealed enrichment of the IL-17 signaling pathway and increased gut microbial abundance of Bacteroidaceae and Tannerellaceae. Vismodegib may alleviate inflammation and tissue damage in COPD by inhibiting NETs-mediated M1 polarization of macrophages. This study is the first to propose the targeting of NET-driven macrophage polarization via Hedgehog inhibition as a novel therapeutic strategy for COPD, providing a new mechanistic framework for drug repurposing.

Systemic administration of influenza virus-specific monoclonal antibodies achieves low concentrations in the nasal mucosa, the portal of infection. Intranasal administration may be more relevant for preventing infection, but the pharmacokinetics of intranasal influenza antibodies is unknown. We present results of preclinical studies and first-in-human phase 1 trials of the intranasally administered CR9114, an anti-hemagglutinin stem antibody that protects against influenza A and B viruses. We tested safety and tolerability of different schedules and doses; pharmacokinetics in nasal mucosal lining fluid of the nose and nasopharynx, saliva, and serum; and ex vivo functionality. We evaluated in vivo efficacy of CR9114 in mice and nonhuman primates. Intranasal CR9114 was safe and well tolerated across all doses and schedules. The half-life of CR9114 in the nose was ~3 hours. Steady-state concentrations were rapidly attained and sustained with multidosing. Trough concentrations were up to 92-fold higher with twice-daily administration compared with once-daily administration. Pharmacokinetics of intranasal CR9114 in nonhuman primates mirrored that of humans better than mice. Postdose nasal samples potently bound hemagglutinin from diverse strains of influenza A and B viruses and, particularly at the 10-milligram dose, neutralized A/H1N1, A/H5N1, and A/H3N2 more potently than baseline samples. Twice-daily administration of CR9114 protected nonhuman primates against influenza virus challenge with the same intranasal formulation and device as used in humans, providing evidence for the efficacy of intranasal multidosing. Together, these study findings characterize the pharmacokinetics of CR9114 after intranasal administration and provide proof of concept that intranasal antibodies can elicit efficacious passive immunity against influenza viruses.

Endothelial dysfunction plays a critical role in the initiation and progression of vascular remodeling and pulmonary arterial hypertension (PAH). Sine oculis homeobox 1 (SIX1) is a developmentally restricted transcription factor, and its expression ceases upon the completion of embryonic development. Deletion of Six1 impairs the differentiation of pulmonary vascular endothelial cells, resulting in pulmonary vascular defects and postnatal death. In this study, we found that SIX1 was increased in the endothelia of pulmonary arteries from patients with PAH and from patients with idiopathic pulmonary fibrosis-associated pulmonary hypertension (PH). Silencing SIX1 using siRNA inhibited hypoxia-induced endothelial dysfunction in vitro, including proliferation, endothelial-to-mesenchymal transition, and endothelin-1 release. Endothelial-specific Six1 knockout improved pulmonary hemodynamics, endothelial dysfunction, pulmonary artery remodeling, and right ventricular function in SU5416/hypoxia (SuHx)-induced PH mice. Moreover, endothelial-specific Six1 overexpression mediated by adeno-associated virus induced a spontaneous PH in wild-type C57BL/6 mice. Structure-based virtual screening and surface plasmon resonance analysis demonstrated that zafirlukast was an inhibitor of SIX1 transcriptional activity. Zafirlukast suppressed hypoxia-induced endothelial dysfunction in vitro and reversed SuHx-induced PH in Sprague-Dawley rats. Mechanistically, multiomics profiling of hypoxia-induced endothelial dysfunction in vitro revealed that microtubule-associated serine/threonine kinase family member 4 (MAST4) was a target of SIX1. MAST4 phosphorylated the Thr^185/202 sites of mitogen-activated protein kinases 1 and 3 (MAPK1/3), resulting in endothelial dysfunction. Overall, we found that SIX1 was a driver for endothelial dysfunction and PH through regulating MAST4 transcription and subsequently MAPK1/3 activation. Targeting SIX1 may be a promising strategy for PAH treatment and drug development.

Leptospirosis is a neglected zoonotic disease caused by bacteria of the genus Leptospira, mainly acquired via direct contact with water and soil contaminated by the urine of infected animals. This is most observed in tropical and subtropical regions, and it is strongly associated with urban population growth in areas lacking adequate sanitation conditions. Leptospira infection can lead to several clinical manifestations in humans, ranging from a nonspecific febrile illness to severe complications such as jaundice, renal failure, and life-threatening pulmonary disease. One of the most severe forms is leptospirosis-associated pulmonary hemorrhagic syndrome (LPHS), characterized by coughing, chest pain, dyspnea, and massive pulmonary hemorrhage. The mortality rate of LPHS is approximately 50%, with death generally occurring within 72 hours after symptom onset. The etiopathogenesis of LPHS remains poorly understood. Some studies suggest that Leptospira spp. may directly damage blood capillaries and alter vascular permeability. Additionally, the host immune response, via the cytokine release, high expression of adhesion molecules, and activation of the Complement System, may further disrupt endothelial integrity, promoting vascular leakage and the systemic dissemination of leptospires. Animal models are essential for a better understanding of Leptospira transmission, colonization, and pathogenesis. This review aims to consolidate current understanding of LPHS, with emphasis on its pathogenesis, immune mechanisms, clinical manifestations, virulence factors, and experimental models.

Although the global burden of pertussis has declined steadily over recent decades, the COVID-19 pandemic coincided with a marked disruption of its established epidemic trajectory. We assessed pandemic-associated changes using spatiotemporal trend analysis, health inequality assessment, multivariable regression, and Mendelian randomization. Globally, the age-standardized disability-adjusted life years (DALYs) rate decreased from 378.01 per 100,000 in 1990 to 70.92 in 2021, accelerating steeply after 2019. Despite reductions, burden remained concentrated in low-sociodemographic index (SDI) countries, with widening relative inequalities. Macro-scale multivariable regression stratified by SDI revealed no robust independent association between COVID-19 and pertussis incidence after adjusting for population density. Consistently, Mendelian randomization analyses found no evidence of a causal effect of genetic liability to COVID-19 on pertussis risk. These findings suggest the pandemic-era decline is driven by disruptions to transmission and health services rather than biological cross-protection. We interpret this transient suppression as contributing to an emerging immunity gap - an accumulation of susceptible individuals following reduced natural exposure and interruptions to routine immunization. As social contact patterns normalize, this immunity gap increases the risk of rebound transmission. Strengthening life-course vaccination, including catch-up programmes and prioritization of low-SDI settings, is essential to mitigate post-pandemic resurgence.

Investigate changes in alcohol consumption and the association between maternal depression and anxiety, considering the moderating effect of social isolation during the COVID-19 pandemic, using a population-based cohort from Brazil.

Data were obtained from the WebCovid-19 study, a web-based follow-up of the 2019 Rio Grande (RS), Brazil, birth cohort, with 1,077 and 1,033 postpartum women participating in waves I and II, respectively. Changes in maternal alcohol consumption were self-reported, while depression and anxiety were assessed using the Edinburgh Postnatal Depression Scale and the Generalised Anxiety Scale. Crude and adjusted negative binomial regression was conducted, including tests for moderation by social isolation.

Of the 781 mothers included, 57.3% reported staying home ≥5 days in the last week, and 5.0% increased alcohol consumption during the pandemic. Median depression and anxiety scores were 8.0 (interquartile range - IQR 3-13) and 6.0 (IQR 3-10), respectively. Mothers who increased alcohol consumption had a 5-point (95% confidence interval - 95%CI 3.0-7.0) and 4.2-point (95%CI 2.6-5.9) increase in depression and anxiety scores, respectively. Social isolation duration did not significantly modify the effect of alcohol consumption on mental health.

Increased alcohol consumption during the pandemic was associated with higher depression and anxiety scores. The hypothesised moderating effect of longer isolation on this association remains a possibility.

Protein biologics are indispensable in disease prevention, diagnosis, and therapy, yet their development remains largely constrained by reliance on native protein scaffolds, resulting in long development timelines, limited structural and functional tunability, challenges in manufacturing consistency, and high production costs.

De novo protein design moves beyond the structural and functional constraints inherent to traditional approaches, enabling the direct creation of proteins with tailored structures and functions and offering a new avenue to address these challenges. In this review, we summarize the principal computational strategies underlying de novo protein design and the contribution of deep learning to its recent progress, and highlight prospective applications, major translational barriers, and the current limitations and future challenges of the field.

Despite notable methodological progress in de novo protein design, its path toward clinical application continues to be limited by a range of biological, technical, and translational considerations. Future work will need closer coordination between computational design, experimental validation, engineering optimization, and clinical needs, with clinical feasibility considered early and refined throughout development.