Mobocertinib, a tyrosine kinase inhibitor approved for EGFR exon 20 insertion-mutated non-small cell lung cancer, induces cardiotoxicity manifesting as QT prolongation. Salidroside, a bioactive compound from Rhodiola rosea, exhibits cardioprotective properties. We investigated electrophysiological mechanisms underlying mobocertinib cardiotoxicity and salidroside's protective efficacy using Langendorff-perfused rat hearts and neonatal rat cardiomyocytes (NRCMs). Hearts were treated with escalating mobocertinib concentrations (214, 428, 856 nM) with or without salidroside (20 μM) pretreatment; cardiac parameters including heart rate, PR, JT, QTc intervals and conduction were mapped via high-resolution multichannel electrophysiology. NRCMs underwent chronic mobocertinib exposure with/without salidroside, followed by transcriptomic sequencing, qRT-PCR, and western blot validation. Mobocertinib concentration-dependently prolonged PR, JT, QTc intervals, increased conduction time/heterogeneity, reduced heart rate/velocity, and JT/QTc prolongation persisted after washout. Salidroside pretreatment markedly attenuated these abnormalities. In NRCMs, mobocertinib prolonged field potential duration and impaired conduction; salidroside normalized parameters. Transcriptomic analysis identified enrichment in calcium signaling, aldosterone synthesis, cGMP-PKG, and adrenergic pathways. Notably, Atp2b2 was upregulated in mobocertinib group but downregulated in salidroside combination group, whereas Agtr1b showed opposite pattern. Thus, salidroside mitigates mobocertinib-induced electrophysiological toxicity by modulating Atp2b2/Agtr1b-related signaling networks, providing a novel cardioprotective strategy against mobocertinib-associated cardiotoxicity.

Drug-induced diffuse interstitial lung diseases are uncommon but potentially severe adverse reactions. Clopidogrel, a widely used antiplatelet agent for the prevention of thromboembolic events, has only rarely been associated with interstitial lung injury. We report the case of a 76-year-old former smoker with a history of dyslipidemia and triple-vessel coronary artery disease who was admitted for chest pain following a recent myocardial infarction. Coronary angiography revealed no new coronary lesions, and antiplatelet therapy was switched from ticagrelor to clopidogrel. Three days after clopidogrel initiation, the patient developed progressive dyspnea (New York Heart Association: NYHA class III), hypoxemia (partial pressure of oxygen or PaO2, 58 mmHg), bilateral crackles, and diffuse interstitial lung involvement with bilateral ground-glass opacities on chest imaging. Infectious, thromboembolic, and other potential etiologies were excluded. Given the close temporal relationship between symptom onset and clopidogrel exposure, together with the exclusion of alternative causes, clopidogrel-induced diffuse interstitial lung disease was suspected. Discontinuation of clopidogrel led to rapid clinical, biological, and radiological improvement within three days. Drug causality assessment was considered probable according to the Bégaud method (C2S2, intrinsic score I3). Although generally well tolerated, clopidogrel should be recognized as a rare but potentially serious cause of reversible diffuse interstitial lung disease. Early recognition and prompt withdrawal of the offending drug may result in rapid recovery and help avoid unnecessary investigations and treatments.

COVID-19 continues to present ongoing global health challenges driven by diverse immune responses and heterogeneous clinical outcomes. The ACCORD trial evaluated 3 investigational treatments-bemcentinib, tozorakimab, and zilucoplan-in patients hospitalized with COVID-19, each of which has demonstrated clinical efficacy. To better understand their molecular mechanisms, we conducted a mechanistic follow-up study, integrating transcriptomic and clinical data from 65 patients and applying cellular deconvolution, differential expression, coexpression, and pathway enrichment analyses to uncover treatment-specific immune responses. Each therapy induced transcriptional shifts and modulated distinct immune pathways implicated in severe disease. Bemcentinib primarily modulated myeloid cell populations and inflammatory signalling; zilucoplan enhanced B-cell signalling and lymphocyte-associated pathways; and tozorakimab exerted broad immune and cellular responses across immune cell types. Co-expression analysis revealed gene networks associated with clinical improvement, each driven by distinct treatment-specific hub genes, indicating diverse regulatory mechanisms across treatments. Improved outcomes correlated with gene expression shifts in 4 key immunological pathways: B-cell signalling, antiviral defense, innate inflammation, and platelet/coagulation activity. In contrast, nonresponders had persistent dysregulation of 1 or more of these gene signatures. Our findings define molecular signatures of treatment response and failure in COVID-19, providing mechanistic insight into how distinct therapies modulate the immune system. These insights support the need for adaptive precision medicine approaches tailored to individual, evolving immune trajectories. Moreover, the immunological mechanisms targeted by these repurposed immunomodulatory therapies may inform treatment strategies across a broader spectrum of immune-mediated diseases beyond COVID-19.

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), for the first time, estimated stillbirth rate (SBR) by the WHO ICD-11 definition (≥22 weeks' gestation) for 204 countries, highlighting the extent of underestimation in stillbirth burden as compared with using only the late gestation (≥28 weeks' gestation) SBR estimation to understand the stillbirth burden. Given the size of its population, India accounted for the highest global burden of stillbirths for both gestation period cut-offs. Given the extent of state-level heterogeneity in disease burden in India, state-disaggregated SBR is necessary to enable policymakers and researchers to tailor strategies that are more responsive to local needs and institutional capacities, thereby enhancing the effectiveness of interventions and related resource allocation.

Exposure to the ambient air pollutant ozone (O3) is associated with adverse respiratory health outcomes. Rodent models have been used to identify mechanisms of response to O3, but their utility has been questioned owing to species differences in physiologic response, most notably exposure-induced hypothermia, which renders rodents relatively resistant to O3 compared to humans.

Immune checkpoint inhibitor (ICI) therapy has become standard of care for late stage non-small cell lung cancer (NSCLC), producing durable responses in a subset of patients. However, inflammatory side eKects termed immune-related adverse events (irAEs) occur in up to 40% of ICI-treated NSCLC patients. Current approaches to alleviate irAEs include treatment with immune-suppressing corticosteroids. However, these treatments may undermine the eKicacy of ICIs by suppressing both the irAE and the anti-tumour immune response. To identify more specific therapeutic targets, a better understanding of the complex immunopathology underlying the development of irAEs in NSCLC is required.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer (LC), offering durable responses in non-small cell lung cancer (NSCLC) and, to a lesser extent, small cell lung cancer (SCLC). Nevertheless, clinical outcomes remain highly heterogeneous, with many patients experiencing primary or acquired resistance and/or immune-related adverse events (irAEs) that impair their quality of life and treatment adherence. The human microbiome, particularly in the gut and oral compartments, has emerged as a critical modulator of systemic antitumor immunity and a promising noninvasive predictive biomarker for ICI efficacy and toxicity. This narrative review synthesizes the current evidence on microbiome composition, diversity, and function in patients with LC receiving ICIs as monotherapy, dual blockade, or in combination regimens, as well as clinically relevant biomarkers associated with treatment response and toxicity. Higher gut microbial alpha diversity and enrichment of beneficial taxa (e.g., Akkermansia muciniphila, Faecalibacterium prausnitzii, and certain Firmicutes) are consistently linked to improved progression-free survival (PFS) and overall survival (OS), mediated by microbial metabolites such as short-chain fatty acids and inosine, which enhance T-cell priming, tumor microenvironment remodeling, and gut-lung axis communication. Microbiome-disruptive exposures, particularly antibiotics and proton pump inhibitors (PPIs), induce dysbiosis and are strongly associated with poorer survival outcomes. Mechanistic insights from preclinical models and clinical cohorts, alongside clinical confounders, underscore the complementary role of the microbiome relative to established markers such as programmed death-ligand 1 (PD-L1) and tumor mutational burden. Prospective standardization of metagenomic profiling and microbiome-modulating interventions represents a key next step in translating these findings into personalized immunotherapy strategies for LC.

Cardiovascular research traditionally relies on animal models or isolated cell cultures, each having limitations in accurately mimicking human heart function and disease. Organ-on-chip technology is the future of translational research studying clinical pathophysiology, drug testing, and personalised medicine. Organs are precisely replicated via their microenvironment and function. This review introduces clinicians to the heart-on-a-chip (HOC) technology, an advanced approach that replicates critical features of the human heart through engineered, microfluidic platforms. HOC models provide clinicians with a more accurate, reliable alternative for studying heart disease and evaluating drug safety, thus reducing dependence on animal testing. The review begins with an explanation of cardiac anatomy and electrophysiology, emphasising their complexities and challenges in traditional modelling. It then describes current advancements in scaffold-based HOC methods, particularly, using decellularised extracellular matrix and innovative techniques such as three-dimensional bioprinting to realistically reconstruct heart tissue architecture and cellular orientation. Special attention is given to electrophysiological considerations, including artificial stimulation methods designed to replicate the heart's intrinsic electrical conduction pathways. The article also discusses significant improvements in real-time and non-invasive monitoring of cardiomyocyte function. By understanding these developments, clinicians will gain insights into how HOC technology can transform cardiovascular research, enhance patient safety by reducing drug-induced cardiotoxicity risks, and pave the way for personalised medicine through patient-specific cardiac models using induced pluripotent stem cells. Ultimately, this review equips clinician readers with the knowledge to understand the milieu of HOC technology, research, diagnostics, and personalised patient care.

Clazosentan, a selective endothelin-A (ET-A) receptor antagonist, is used to prevent cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Although pulmonary edema and fluid retention are recognized adverse effects, hypoxemia associated with atelectasis has not been described. Endothelin-1 contributes to hypoxic pulmonary vasoconstriction (HPV), which preserves ventilation-perfusion (V/Q) matching by diverting blood flow from poorly ventilated regions; pharmacologic ET-A blockade may attenuate HPV, increasing intrapulmonary shunt and impairing oxygenation. We report a man in his 60s with aneurysmal SAH (World Federation of Neurosurgical Societies [WFNS] I, Fisher 3) who underwent clipping surgery and postoperative clazosentan infusion (10 mg/h, standard Japanese dosage). On day 7 of infusion, hypoxemia (SpO2 < 90% room air) developed; on day 8, arterial blood gas showed PaO2 62.5 mmHg with a PaO2/FiO2 (P/F) ratio of 109. Chest computed tomography (CT) demonstrated right lower-lobe atelectasis without pulmonary edema or pleural effusion, and echocardiography showed normal cardiac function. Clazosentan was discontinued and corticosteroid therapy initiated, after which oxygenation improved and the atelectasis resolved. The patient was extubated on day 18 and discharged with good neurological recovery. This case illustrates a plausible mechanism whereby ET-A receptor blockade suppresses HPV, exacerbating V/Q mismatch in the presence of segmental atelectasis. Improvement after drug withdrawal supports this association. Clinicians should recognize that hypoxemia during clazosentan therapy may occur independently of fluid overload and warrants early respiratory evaluation.

Cellular stress is implicated in the progression of lipopolysaccharide (LPS)-evoked acute lung injury (ALI). The goal of this study was to evaluate the effect of oral supplementation with rosiglitazone (RSG), which is an agonist of peroxisome proliferator-activated receptor (PPAR)-γ, on pulmonary inflammatory response, oxidative stress, and endoplasmic reticulum (ER) stress during LPS-evoked ALI in mice. The mice were randomly divided into four groups and orally supplemented with or without RSG (10 mg/kg) once daily for 5 consecutive days before LPS (1 mg/kg) intraperitoneal injection. The mice were sacrificed at 12 h after LPS injection. As expected, LPS-evoked ALI and death were attenuated in mice that were pretreated with RSG. LPS-evoked increase in chemokines (KC, MIP-2, and MCP-1) and proinflammatory cytokines (TNF-α and IL-1β) was inhibited in the mouse lungs by RSG. RSG pretreatment significantly mitigated LPS-evoked nuclear translocation of NF-κB p65 and p50, which regulate inflammatory gene transcription in the lungs. Additionally, LPS-evoked glutathione depletion and lipid peroxidation were alleviated by RSG. The abnormal expression of NADPH oxidases and antioxidant enzymes was restored in the lung tissues by RSG. Further experiments revealed that LPS-evoked upregulation of GRP78, p-IRE1α, and p-EIF2α was blocked by RSG pretreatment. Mechanistically, RSG pretreatment enhanced PPARγ activity in the mouse lungs and bronchial epithelial cells. RSG promoted the interaction between NF-κB p65 and PPARγ in the mouse lungs. Overall, RSG pretreatment protects against LPS-evoked ALI partially through enhancing PPARγ activity and inhibiting the cellular stress response in the mouse lungs.