Medicine and Pharmacology

Abstract: Background: Severe Type 2 (T2)-high eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) reflect a unified airway inflammatory continuum. Real-world, long-term (3-year) data evaluating dual-airway effectiveness and global clinical remission remain scarce. Methods: This single-center, real-world cohort study evaluated 88 patients with severe uncontrolled T2-high eosinophilic asthma receiving subcutaneous mepoli-zumab (100 mg every 4 weeks) over 156 consecutive weeks. Outcomes were assessed at baseline, 52 weeks, and 156 weeks. Dual-airway benefits were analyzed in a comorbid CRSwNP subgroup (n=51) using SNOT-22, Bilateral Nasal Polyp Score (NPS), and smell loss Visual Analogue Scale (VAS) against 2026 EUFOREA global remission criteria. Results: Mepolizumab induced sustained control over 3 years. Mean ACT scores improved from 13.63±3.94 (baseline) to 21.53±3.01 at 156 weeks (p< 0.0001). Annual exacerbations decreased by 85.5% at Year 3 (0.48±0.61 events/year; p< 0.0001). Daily oral corticosteroid maintenance fell by 81.9% (p=0.027). FEV₁ increased by +241 mL at Year 1 and remained completely stable through Year 3 (2625±797.5 mL). Parallel improvements occurred in SNOT-22, NPS, and VAS scores within the CRSwNP subgroup, meeting global remission benchmarks. Conclusion: Continuous 3-year mepolizumab delivers synchronized dual-airway benefits, preserves long-term lung function, minimizes oral corticosteroid reliance, and achieves high rates of multidimensional global airway remission.

Abstract: Background. Mycoplasma pneumoniae, the archetypal agent of “walking pneumonia”, causes predominantly self-limited infection peaking in school-age children and adolescents, and is regarded as rarely fatal. After near-disappearance under pandemic non-pharmaceutical interventions in 2020–2021, re-emergence was delayed relative to other respiratory pathogens but was well established by 2023–2024. No standalone global estimate of M. pneumoniae–attributable mortality spanning the pandemic window has been reported to contextualise this resurgence. Methods. We analysed Global Burden of Disease (GBD) Study 2023 estimates (release v8352), which attribute lower respiratory infection (LRI) deaths to 26 pathogens through a counterfactual, population-attributable-fraction framework. Attributable deaths (the only available measure) were extracted globally and for seven super-regions, 1990–2023, for children aged 0–19 years (under 5, 5–9, 10–14, and 15–19 years). Trends were summarised by estimated annual percentage change (EAPC); 95% uncertainty intervals (UIs) were propagated conservatively. Reporting follows the GATHER statement. Results. In 2023, an estimated 26,382 deaths (95% UI 18,984–36,012) in children aged 0–19 years were attributable to M. pneumoniae, ranking ninth among 26 LRI aetiologies and accounting for 3.71% of all-pathogen LRI deaths. Deaths fell by 50.7% from 1990 to 2023 (EAPC −2.45% per year, 95% CI −2.66 to −2.23). Sub-Saharan Africa and South Asia carried 81.6% of the 2023 total. The 5–14 year share of attributable deaths was 15.0%, versus 2.2% for respiratory syncytial virus. Children under 5 years accounted for 80.6% of attributable deaths. Across the pandemic window, deaths fell only 17.1% in 2019–2021—versus 62.6% for influenza and 65.2% for respiratory syncytial virus—then rebounded 16.1% by 2023, exceeding the no-pandemic trend extrapolation by 19.2%. The crude mortality rate fell faster than counts (EAPC −2.93% per year), and estimates were stable across GBD rounds (≤2.6% difference for under-5 deaths).Conclusions. Modelled M. pneumoniae mortality concentrates where macrolide-resistance data and diagnostics are scarcest; its school-age skew and post-pandemic rebound are coherent with surveillance. These estimates provide baselines for age-targeted empirical-treatment guidance and resistance-aware stewardship.

Abstract: Background. Pulmonary fibrosis encompasses a heterogeneous group of interstitial lung diseases (ILDs) characterized by progressive remodelling and scarring of the lung parenchyma. Although environmental and clinical factors contribute substantially to disease development, increasing evidence indicates that genetic susceptibility plays a central role in determining individual risk, disease phenotype, age at onset, and clinical outcome. Methods and objectives. This narrative review provides an interpretative overview of the genetic mechanisms underlying pulmonary fibrosis, focusing on familial pulmonary fibrosis (FPF), major susceptibility genes, and the clinical implications of genetic testing. Results. Familial pulmonary fibrosis, generally defined by the occurrence of pulmonary fibrosis in at least two relatives within the third degree of relationship, represents approximately 20% of pulmonary fibrosis cases and is frequently characterized by earlier disease onset and a more aggressive clinical course than sporadic disease. The genetic architecture of pulmonary fibrosis is complex, involving both common and rare genetic variants, with telomere maintenance and mucin regulation representing key biological pathways underlying disease susceptibility, although identifiable causal variants are found in only approximately 25% of affected families. In parallel, common genetic variants, particularly the MUC5B promoter variant rs35705950 and variants in TOLLIP, contribute to disease susceptibility and may influence disease progression and treatment response. Conclusion. The increasing availability of genetic testing has important implications for diagnosis, family screening, prognosis and potentially treatment selection. Integrating genetic sequencing with telomere length assessment may provide complementary information and contribute to a more individualized approach to patients with pulmonary fibrosis.

Abstract: Background/Objectives: Life-threatening haemoptysis primarily fatal due to airway obstruction, and the culprit vessel must be identified before it can be occluded. Bronchial artery embolisation (BAE) is the established haemostatic treatment, yet its success is largely determined upstream, by the accuracy of the diagnostic chain that precedes it: computed tomography angiography (CTA), bronchoscopy and selective angiography. These modalities are conventionally deployed sequentially and by separate teams. Case Presentation: An 84-year-old male patient presented with abrupt life-threatening haemoptysis. CTA demonstrated an ectatic left bronchial artery with arterial-phase venous opacification, diagnostic of a bronchial arteriovenous fistula (BAVF). Because this phenotype determines both the embolic agent and the definition of technical success, bronchoscopy and angiography were performed concurrently. Endoscopy localised pulsatile bleeding to the left upper lobe bronchus and secured the airway; superselective angiography confirmed the fistula, which was occluded with detachable platinum microcoils under continuous endoscopic observation. Conclusions: Outcome in life-threatening haemoptysis depends less on the embolic device than on whether imaging, endoscopy and angiography operate within a single decision-making environment. We propose a phenotype-driven, dual-endpoint workflow, supported by a structured CTA reading checklist and an embolic-agent selection framework, as a reproducible model for the multidisciplinary management of pulmonary vascular emergencies.

Abstract: Respiratory pathogens infect children in a reproducible age order: respiratory syncytial virus (RSV) and pertussis dominate the first months of life, human bocavirus and adenovirus peak in toddlers, Mycoplasma pneumoniae pneumonia peaks at school age, rhinovirus and influenza infect all ages, and several of these pathogens resurge in older adults. Here we compile and organize the published evidence behind these patterns, treating each pathogen’s characteristic age window as a read-out of its immune mechanism within the classical age-structured tradition. Two interacting “clocks” organize the pediatric spectrum. The first is the maternal-antibody umbrella: transplacental IgG decays by infant catabolism, and the protective trough at 2–6 months is set by the distance between the starting titer and a protective threshold, measured in half-lives, rather than by any single half-life; maternal RSVpreF and Tdap vaccination and passive nirsevimab prophylaxis provide trial-level causal proof that this clock sets the infant window. The second clock is the cumulative acquisition of type-specific immunity, which closes the toddler windows of bocavirus and adenovirus but never closes for antigenically diverse rhinovirus or drifting influenza; since exposure accumulates on a similar schedule, this clock is only partially identifiable serologically. M. pneumoniae is the decisive boundary case: a single maternal clock under a constant force of infection cannot place a peak at school age—a known structural property of age-structured transmission models, no new simulations performed—so delayed first sensitization, waning partial immunity, and immunopathology on reinfection are required. For encapsulated bacteria, a “polysaccharide trap”—poorly transferred IgG2-dominated maternal antibody plus developmental T-independent unresponsiveness before age two—explains the earliest bacterial windows. We also synthesize breast-milk, innate-immune and microbiome modifiers of both clocks, and an adult “third clock” of immunosenescence. The framework yields falsifiable predictions for immunization timing and disease patterns in immunocompromised hosts.

Abstract: Point-of-care ultrasonography (POCUS) has emerged as a diagnostic tool in pulmonary medicine, offering real-time bedside assessment of respiratory pathologies. This narrative review examines the current applications of POCUS in pulmonary practice, evaluates its diagnostic accuracy compared to traditional imaging modalities, and explores future directions for this technology. POCUS demonstrates superior sensitivity to chest radiography for detecting pneumonia, pleural effusion, pneumothorax, and pulmonary edema, with diagnostic accuracy approaching that of computed tomography in some clinical scenarios. Key applications include evaluation of acute dyspnea, monitoring of mechanically ventilated patients, guidance of therapeutic interventions, and assessment of diaphragmatic function. Despite its advantages, POCUS requires adequate training and has limitations in some clinical contexts, particularly in ventilator-associated pneumonia and when used as a replacement rather than adjunct to standard diagnostic pathways. Emerging applications include artificial intelligence-assisted interpretation, integration into telemedicine platforms, and expanded use in outpatient pulmonary clinics. As portable ultrasound technology continues to advance and training programs become more standardized, POCUS is positioned to become one of the key components of the pulmonary physician’s diagnostic tools.

Abstract: Background: The granuloma is the defining lesion of sarcoidosis, yet the internal architecture of the non-necrotising lesion — and whether the homeostatic CD10/MME+ macrophage identity enters it — is unresolved in lung.Objectives: To map the programme-level spatial anatomy of the sarcoidosis granuloma and test prespecified cross-disease predictions.Methods: We analysed 10x Visium spatial transcriptomes of three sarcoidosis lungs and one healthy control (GSE262998), four TSC1/2-deficient granuloma-model mouse lungs (GSE263088) and two validation cohorts (nine explanted sarcoidosis lungs, GSE288607; four tuberculous granuloma sections, GSE296400). Granuloma spots, partitioned into core, rim, mid and far zones, were scored for 25 macrophage modules and 49 convergence signatures.Results: A quadripartite programme — antigen presentation (core 1.48–1.80 vs 1.02–1.28), iron handling (1.30–1.45 vs 0.68–1.22), lysosomal mass (0.69–0.95 vs 0.19–0.51), cell fusion (+0.07 to +0.22 core−far in 3/3 sections) — peaked at the core in all three sarcoidosis sections, while hypoxia was flat, unlike the hypoxic-necrotic tuberculosis archetype; the gradients survived density matching, and deconvolution attributed 59–74% of core elevations to per-spot macrophage content (i.e., 26–41% of the elevations reflect per-cell state change rather than composition). The CD10/MME+ identity was not consistently recruited (core MME 0.22 versus 0.38 at far in one section; weak, inconsistent enrichment in two). All four programmes replicated across 80 sarcoidosis nodules (median Δz +0.20 to +0.52; hypoxia +0.03); tuberculous caseous cores displayed perinecrotic hypoxia cuffs with fusion depleted in the caseum (and not enriched in the viable cuff), and the prespecified foam check was falsified (sarcoidosis-strong).Conclusions: The sarcoidosis granuloma is a centripetally organised, perfusion-preserving antigen-sequestration niche without hypoxia; the homeostatic CD10+ identity is not a consistent niche component.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease associated with mitochondrial dysfunction. Mitochondrial transplantation (MTx) has recently emerged as a promising regenerative medicine strategy for diseases associated with mitochondrial dysfunction. Growing evidence supports the therapeutic potential of MTx in pulmonary fibrosis. Preclinical studies have demonstrated that the delivery of healthy mitochondria can improve mitochondrial function, reduce fibrotic responses, and restore cellular homeostasis in experimental models of lung fibrosis. However, the available evidence is largely limited to in vitro and animal studies, each of which captures only select features of IPF and fails to fully reproduce the complexity of human disease. Consequently, the translation of these promising findings into clinical therapies remains challenging. To better understand the opportunities and limitations of MTx in IPF, this paper examines the experimental platforms currently used in the field. The physiological relevance, translational value, and ability to bridge the gap between mechanistic discovery and clinical application are given. The selection of appropriate experimental models is critical for advancing the field. Each platform offers distinct advantages and limitations. Combining complementary platforms may provide the most effective strategy for evaluating mitochondrial-based therapies and accelerating clinical translation.

Abstract: Background: In interstitial lung disease (ILD), alveolar macrophage loss and SPP1+ expansion have been described separately; the lost side (the homeostatic reservoir) is rarely quantified on a common scale or at donor level. We tested whether ILD remodels the lung macrophage ecosystem as a bipolar displacement of relative composition.Methods: A 25-module functional/morphological scoring system was applied to three scRNA-seq atlases (Madissoon normal lung, 40,634 myeloid cells; a PBMC reference; the Natri ILD atlas, 175,426 cells, 118 donors, 10 diagnoses, 30 microclusters), normal-lung Visium sections, 195,994 ligand-receptor edges and the independent IPF Cell Atlas (GSE136831), with donor-level statistics as the primary inferential unit.Results: Interstitial macrophages (IMs) were the most reprogrammed compartment, losing complement/phagocytic identity (up to -0.39) while gaining granuloma and matrix-remodelling programmes; sarcoidosis was the exception (complement +0.08; antigen presentation +0.31). C1Q-high reservoir microclusters, CD10/MME-high in their lipid-handling branch, contracted at donor level across all powered diagnoses, with disease-specific expansion of SPP1+ states; in IPF, donor-level tests supported a candidate SPP1/CHIT1-high state (mc26, 5.3% versus 0.39%; p=1.6×10-9; microcluster boundaries seed-sensitive) and a candidate OCSTAMP+ fusion-primed IM state. Ligand-receptor analysis indicated strengthened FN1-ITGB1/SPP1-CD44 axes and attenuated THBS1-CD36/C3 circuits; spatial data showed dispersed, non-aggregated homeostatic behaviour in normal lung; the expanding pole and the compositional anticorrelation replicated in the independent cohort, whereas programme-level identity loss did not.Conclusions: The ILD macrophage ecosystem exhibits a bipolar displacement of relative composition: a testable model of homeostatic-niche dissolution and pathological-niche construction.

Abstract: Image-guided thermal ablation has matured into a recognized local therapy for medically inoperable early-stage non-small cell lung cancer and selected pulmonary metastases, and transbronchial approaches delivered through navigational bronchoscopy are now extending ablation to patients who cannot tolerate pleural puncture. Yet ablation planning remains strikingly empirical: target coverage is estimated from manufacturer-provided geometric charts derived from ex vivo or non-pulmonary tissue, while the two features that most distinguish the lung from other ablated organs, respiratory motion and the low thermal and electrical conductivity of aerated parenchyma, are handled by operator experience rather than by patient-specific modeling. Digital twin (DT) technology, defined here as a patient-specific computational replica coupled to its physical counterpart through bidirectional data flow, offers a framework to close this gap. In this narrative review we (i) summarize the clinical maturity of percutaneous and transbronchial lung ablation that makes planning the rate-limiting step; (ii) propose a three-tier terminological hierarchy (static model, digital shadow, and digital twin) to discipline a literature in which the term is increasingly diluted; (iii) map a four-layer technical stack for a lung ablation DT, spanning four-dimensional anatomical modeling, respiratory-motion compensation, energy–tissue coupling simulation, and intraoperative closed-loop updating, and show that every layer already has validated components in adjacent fields, including a biophysical DT of liver microwave ablation, histology-validated dielectric characterization of human lung carcinoma, and retrospective computational validation of lung microwave ablation models against post-treatment imaging; and (iv) outline a staged validation pathway and a five-item research agenda, arguing that the first integrated, closed-loop DT for pulmonary ablation, percutaneous or transbronchial, remains to be built, and that the specialty which builds it will define the next standard of ablation planning.

Abstract: Background: Advanced interventional pulmonology (IP) increasingly depends on cone-beam computed tomography (CBCT) and hybrid imaging workflows for the diagnosis and management of intrapulmonary lesions. However, globally, many IP teams still lack a dedicated pulmonology procedure suite in their institution and instead perform cases in rooms originally designed for cardiovascular, neurovascular, interventional radiology, or surgical use. Methods: This review evaluates ceiling-mounted single-plane systems, floor-mounted systems, older and newer biplane angiography suites, robotic CBCT hybrid operating room systems and mobile CBCT systems and their suitability for IP procedures. Results: Based on available literature and institutional experience, ceiling-mounted single-plane systems may offer ergonomic advantages for bronchoscopic IP because they preserve head-side access and procedural ergonomics. Floor-mounted systems remained usable, particularly in older institutions, but could restrict airway-side positioning. Biplane-suite capabilities varied by system generation and configuration; some newer configurations provided CBCT and overlay functions that may facilitate pulmonary workflows. Robotic hybrid systems may provide broad procedural flexibility for complex and combined procedures but require greater institutional support. Mobile CBCT systems represented a practical entry strategy for centers without dedicated infrastructure, while conventional multidetector CT remained valuable for selected percutaneous interventions. Successful adaptation across all platforms depended on room layout, workstation capability, team familiarity, anesthesia support, and multidisciplinary collaboration. Conclusions: Advanced IP programs can be developed without a purpose-built pulmonology suite. Careful adaptation of existing imaging environments may allow centers to expand precision bronchoscopic and percutaneous capabilities according to local resources and workflow realities.

Abstract: Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease characterized by excessive deposition of extracellular matrix and progressive destruction of the lung architecture. Repeated epithelial injury and aberrant tissue repair are strongly associated with its pathogenesis; however, the molecular mechanisms underlying disease progression remain incompletely understood. Altered microRNA (miRNA) expression has been extensively associated with IPF, but comparatively little attention has been given to the mechanisms regulating miRNA maturation and processing during pulmonary fibrosis. Objective: In this narrative review, we aimed to describe the relationship between IPF pathogenesis and alterations in miRNA maturation, with particular emphasis on post-transcriptional mechanisms that may disrupt the production and function of mature miRNAs. Methods: We conducted a narrative review of the available literature using PubMed, Scopus, and Google Scholar. No specific time frame was established because of the limited number of studies directly addressing miRNA maturation in IPF. Original research articles were prioritized, while relevant studies describing miRNA maturation mechanisms in other biological and disease contexts were also considered to provide mechanistic insight. Results: The available evidence suggests that alterations in miRNA maturation may contribute to miRNA dysregulation in IPF beyond changes in transcriptional control. Disruption of the Drosha/DGCR8 microprocessor complex, altered Dicer-dependent processing, and post-transcriptional modifications of miRNA precursors may affect the production of mature miRNAs. In addition, adenosine-to-inosine editing mediated by adenosine deaminases acting on RNA (ADARs) may modify miRNA sequences and influence their maturation, stability, and target selection. Mechanotransduction-associated pathways, including Hippo/YAP signaling, may further interfere with the miRNA-processing machinery. These alterations may contribute to the persistent dysregu-lation of antifibrotic miRNAs, including miR-29, thereby promoting extracellular matrix accumulation and sustaining profibrotic signaling. Conclusions: Although evidence directly linking defects in miRNA maturation to IPF remains limited, available findings support the hypothesis that alterations in post-transcriptional miRNA processing represent an additional regulatory layer contributing to pulmonary fibrosis. Further experimental studies are needed to determine how specific alterations in miRNA maturation and editing contribute to IPF pathogenesis and whether components of the miRNA-processing machinery may represent potential therapeutic targets.

Abstract: Background: A dual-axis organization of non-alveolar macrophages—scar-associated SPP1+ and tissue-resident-like FOLR2+ populations—was recently delineated in idiopathic pulmonary fibrosis (IPF), but their functions and niches remain unresolved. Methods: We integrated full-transcriptome re-clustering of the GSE135893 myeloid compartment, independent replication (GSE136831), and GeoMx spatial profiling of bronchiolitis obliterans and fibrosing ILD lesions (GSE316672, GSE255174). Results: Two IPF-emergent entities were confirmed and first systematically quantified: SPP1+/TREM2+ scar-associated macrophages (97% IPF-derived; 4.0% to 30.7% of macrophages) and the FOLR2+/CD163+/SLC40A1+ iron-handling population (95% IPF; 11.9% to 19.0%). Both axes replicated in the Adams cohort (donor-level p = 1.2 × 10⁻⁵ and 8.2 × 10⁻¹¹). Spatial profiling revealed a core-and-ring architecture in BO lesions (SPP1+/TREM2+ luminal core; MCL1-high scavenger ring). Monocyte flux correlated with fibroblast apoptotic priming (rho = +0.54; nominal p = 0.045). No canonical M1/M2a enrichment was detected; the FOLR2+ efferocytosis arm was MERTK/GAS6-dominant across cohorts. Conclusion: The fibrotic lung’s dual-axis macrophage architecture is functionally attributed and spatially resolved, with implications for combination targeting.

Abstract: Background: Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease in which apoptosis-resistant fibroblasts drive progressive scarring. Fibrotic mesenchymal cells are functionally “primed for death”, but the transcriptional architecture of apoptotic priming in the human IPF fibroblast lineage—and its dominant anti-apoptotic dependency—remains undefined. Methods: We reanalyzed the 114,396-cell GSE135893 atlas [1], scoring 2,653 fibroblast-lineage cells for pre-specified pro- and anti-apoptotic BCL-2-family modules and a composite Apoptosis Index, with donor-level replication in GSE136831 [2] and cell-level confirmation in two further cohorts. Results: In IPF fibroblasts, the anti-apoptotic (cell-level p = 3.0 × 10⁻²¹; d = 0.66) and caspase modules were elevated and the Apoptosis Index shifted toward survival, with MCL1 the dominant anti-apoptotic transcript (log2FC = +1.84; 91.3% versus 63.0% of cells)—an elevation driven substantially by disease-emergent subtype composition (93.5–100% detection, near-absent in control); depth-matched within-state difference attenuates (65.6% versus 62.1%, ns). Cell-level p-values are descriptive; donor-level analyses are the primary inference. The double-high “primed” fraction was elevated in IPF (25.6% versus 11.6%; cell-level p = 2.6 × 10⁻⁴; nominal at donor level, p = 0.023), concentrated in disease-emergent subsets; threshold-sensitivity and module-arm decoupling showed it is driven by the anti-apoptotic arm alone: the fibroblast pool is survival-protected, not genuinely primed, while pro-apoptotic loading emerged only upon myofibroblast differentiation (p = 1.1 × 10⁻⁸)—a two-stage architecture: protected fibroblasts give rise to primed, death-leaning myofibroblasts. Module-level elevations were donor-level null (p = 0.30–0.43); the supported findings are the donor-level primed-pool expansion (Habermann nominal p = 0.023; GSE136831 nominal p = 0.0068) and the compositional MCL1 elevation, with cell-level confirmation in two further cohorts. Conclusions: Apoptotic priming along the IPF fibroblast–myofibroblast lineage is a two-stage program dissected at single-cell resolution, nominating MCL-1 as an antifibrotic target warranting protein-level and pharmacological validation.

Abstract: Single-cell atlases have resolved the fibroblast compartment of idiopathic pulmonary fibrosis (IPF) into discrete subtypes [1], but subtype-resolved secretory output and surface-marker logic for prospective isolation remain incompletely defined. We re-analyzed the Habermann et al. single-cell atlas of fibrotic lung (GSE135893; 114,396 cells, including 3,605 fibroblast-lineage cells, of which 2,653 IPF/control cells entered the main contrasts) [1], quantifying detection rates and mean expression of 72 secreted genes and 16 candidate surface markers across four curated subtypes, validated by full-transcriptome re-clustering. Inflammatory chemokine production was concentrated in HAS1-high fibroblasts (CXCL2 in 70.4% of cells, CXCL8 in 46.9%), whereas PLIN2+ fibroblasts carried an angiogenic bias (VEGFA 65.6%). CSF1 was silenced upon myofibroblast differentiation irrespective of diagnosis (fibroblasts 34.2–48.6% versus myofibroblasts 8.7–14.8%), a differentiation-linked rather than disease-specific switch, and the interferon-γ–inducible chemokines CXCL9, CXCL10 and CXCL11 were detected in only 0.0–2.6% of cells across subtypes (maximum 2.6% = CXCL9, 5/196 control myofibroblasts). A CD34-low/PDPN-high/CD73-high/FAP+ panel resolved all four subtypes at the marginal transcript level (pending joint, antibody-level validation), whereas CD90 lost discriminatory value in disease. CD10 (MME) marked a control-enriched, putatively resolving myofibroblast state that contracted from 23.0% to 5.4% in IPF; its interleukin-4 induction was tested across cohorts and remains unresolved. Key findings replicated in two independent cohorts (GSE136831; GSE122960) and were spatially corroborated by GeoMx profiling (GSE255174), while CSF1 and compartment-level chemokine effects varied across cohorts. Fibroblast subsets thus carry distinct, isolable secretory identities in IPF, providing a transcriptome-resolved resource for protein-level and spatial validation of fibroblast functions in fibrotic lung.

Abstract: Background: Upper respiratory infections (URIs) are the most frequent illnesses of childhood, yet mortality-anchored child-health monitoring excludes high-frequency, low-fatality conditions. No dedicated pediatric assessment of the global URI burden exists for the Global Burden of Disease Study (GBD) 2023. We quantified URI incidence and mortality at ages 0–19 years, 1990–2023. Methods: We extracted deaths and incident episodes for the GBD cause “upper respiratory infections” from the GBD 2023 Results Tool for the under-5 aggregate plus the 5–9-, 10–14-, and 15–19-year bands, 21 regions, and five Socio-demographic Index (SDI) quintiles, 1990–2023. Crude rates used back-calculated populations; trends used estimated annual percentage change (EAPC). URI was positioned against diarrhoeal diseases, asthma, lower respiratory infections (LRI), and tuberculosis. Results: In 2023, URIs caused 5.616 billion incident episodes (95% uncertainty interval [UI] 4.133–7.330 billion) at ages 0–19 years—210,275 per 100,000, about 2.1 episodes per child per year—against 16,382 deaths (1,781–57,834), a case-fatality proxy of 0.00029%. URIs outnumbered LRI episodes 69.3-fold, while LRI deaths exceeded URI deaths 43.4-fold. Since 1990, incident episodes rose 9.8% in number while the rate declined only 7.3% (EAPC −0.27% per year, one-eleventh of the LRI pace); deaths fell 39.6% (rate EAPC −1.90%). Under-5 children accounted for 34.5% of episodes (three per child per year) and 85.7% of deaths. Incidence rates were nearly flat across SDI quintiles (183,913–255,578 per 100,000), whereas mortality fell 66-fold from low to high SDI (1.724 vs 0.026 per 100,000); the low-SDI quintile carried 89.2% of deaths. Conclusions: The world’s most common pediatric infection is also its least monitored: incidence has stalled for three decades, while a small but real mortality toll concentrates in under-5 children in low-SDI settings. URI merits inclusion in child-health monitoring as a morbidity and antibiotic-stewardship indicator and improved cause-of-death certification where fatal respiratory illness is coded to the upper airway.

Abstract: Background: Lower respiratory infections (LRIs) remain the leading infectious cause of child death, yet global frameworks focus on under-5s and the 5–19-year burden lacks systematic quantification. We analyzed the 0–19-year LRI burden in the Global Burden of Disease Study (GBD) 2023.Methods: We extracted deaths, DALYs, YLDs, incidence and prevalence for 204 countries, 1990–2023, from the GBD 2023 Results Tool for the official <5-year aggregate plus three older pediatric bands. We computed trends, Socio-demographic Index (SDI) gradients and pandemic-window changes; defined a national episode-fatality ratio proxy (EFR; deaths per 1,000 incident episodes); extrapolated trends to 2030; tested whether school-age mortality divergence tracks pediatric tuberculosis burden; and decomposed deaths into the 26 etiologic fractions.Results: In 2023, LRIs caused 711,713 deaths (95% UI 579,607–843,819), 62.49 million DALYs and 81.05 million incident episodes at ages 0–19 years. The EFR varied 75.6-fold across countries—three times the 25.9-fold national range of incidence—tracked income and, independently, inequality, and widened between low- and high-SDI settings over 1990–2023; incidence and fatality were positively correlated across countries (r = 0.66), and a best-quartile counterfactual implied 80.1% of deaths avertable (upper bound). The global EFR rose silently by 30.4% between 2010 and 2019. Improvement was age-asymmetric: in crude-rate terms, mortality fell 69.1% under 5 years but 39.4% at ages 5–19 years; the 5–19-year share of deaths rose from 6.7% to 14.4%, reaching 16.5% by 2030. Divergence was widest where under-5 progress was fastest and did not track pediatric tuberculosis burden. Streptococcus pneumoniae caused 32.0% of 2023 deaths (47.8% in 1990); influenza and RSV deaths collapsed into 2021 and rebounded fastest thereafter, remaining below 2019. Low-SDI countries carried 61.7% of deaths at 22 times the high-SDI rate. Post-2021 patterns were directional only.Conclusions: Fatality inequality—wider than, and positively correlated with, exposure inequality—now defines the divide, and progress has concentrated under age 5, leaving school-age children and adolescents behind. We propose the EFR as a monitorable indicator, with layered responses: surveillance extension to ages 5–19 years, clinical targeting of high-risk groups, and case-management strengthening in high-burden regions—without routine adolescent vaccine expansion, which current data do not support.

Abstract: Background Post-pandemic resurgence of childhood respiratory pathogens has been documented by case-based surveillance, but case counts are sensitive to testing behaviour. Whether the mortality rebound is uniform or structured is unknown. We phenotyped the 2019–2023 collapse and rebound of modelled childhood deaths from 29 respiratory infectious causes across 204 countries.Methods We assembled a country × cause panel of Global Burden of Disease Study 2023 death estimates at ages 0–19 years (26 lower-respiratory-infection aetiologies, tuberculosis, pertussis and COVID-19). For each cell we defined collapse (2019→2021), rebound (2021→2023) and net change (2019→2023), classified the 1,917 stable cells (2019 deaths ≥20; 1,800 non-COVID-19 and 117 COVID-19) into six phenotypes using declared thresholds, and handled COVID-19 separately as a peak-fade metric. Reporting follows GATHER.Findings The rebound was phenotypically structured, not uniform. Pertussis rebounded in 85 of 87 evaluable countries (98%; median +168%) yet only 32% exceeded their 2019 baseline—a rebound without overshoot, excess concentrated in sub-Saharan Africa. Influenza and respiratory syncytial virus showed a near-universal V-with-shortfall: fast rebound in 70.5% and 72.5% of countries, but median net change near −50%. Only Latin America and the Caribbean sat above baseline, marginally (+0.9%), against −17.0% in high-income countries. COVID-19 deaths faded by a median 73%, resurging in six countries, five late-exit settings. Pneumococcal rebound was uncorrelated with conjugate-vaccine coverage (ρ = 0.00).Interpretation Post-pandemic mortality rebounded as distinct, geographically structured phenotypes, not a single global wave; mortality readouts complement incidence surveillance and locate where the rebound window remains open.

Abstract: Background Global child pneumonia strategy increasingly asks whether marginal resources should go to completing vaccine programmes or to hospital platform investments. The answer cannot be uniform across countries. We operationalised this question as a country-level priority typology for 204 countries, treating the vaccine policy dimension, coverage with pneumococcal conjugate vaccine (PCV), Haemophilus influenzae type b (Hib) vaccine, and diphtheria-tetanus-pertussis vaccine (DTP), as a first-order input to classification rather than an after-the-fact check. Methods We combined Global Burden of Disease Study 2023 estimates of deaths from 29 pneumonia-relevant pathogens in ages 0–19 years for 204 countries in 2023, each pathogen assigned to a dominant intervention channel (vaccine-reachable, mixed, platform-sensitive) under previously published rules, with WHO/UNICEF Estimates of National Immunization Coverage (WUENIC) for PCV3, Hib3, DTP3 and BCG, and with WHO vaccine-introduction records. An EPI coverage index (mean of PCV3 and Hib3) summarised conjugate-vaccine programme strength. Countries were classified by declared thresholds into low-burden (<500 deaths), vaccine-priority (vaccine-channel share ≥40% and EPI index <80%), platform-priority (platform share ≥50%), or mixed-transitional. Vaccine residual space was computed as vaccine-channel deaths multiplied by the coverage gap. Robustness of the typology was verified by bootstrap resampling of the 204 countries (500 replicates; all four types perfectly stable, mean Jaccard 1.00, because classification is a deterministic per-country rule) and by ±5 percentage-point sensitivity on all three declared thresholds, which reclassified 4–11 countries (2.0–5.4%) per threshold (Supplementary Text S9, Tables S9–S10). Findings In 2023 the 29 pathogens accounted for 964,615 deaths: 45.7% vaccine-reachable, 13.1% mixed and 41.1% platform-sensitive. Thirty-two vaccine-priority countries carried 51.8% of all deaths; within them, 20 urgent-stratum countries (EPI index <60%) carried 209,807 deaths and 12 completion-stage countries (60-80%) carried 289,607. Ten vaccine-priority countries, including China, had not introduced PCV nationally, representing introduction space rather than within-programme coverage gaps. Forty-seven countries with DTP3 coverage below 80% carried 62.6% of global pertussis deaths. Eighteen platform-priority countries carried 7.8% of deaths; the same two pathogens (Klebsiella pneumoniae, Pseudomonas aeruginosa) led the platform channel across high-burden settings. Across the 2019-2023 pandemic window, the largest single-country share movements pushed platform shares down as COVID-19 entered the vaccine channel, but across the full set of 82 countries with at least 500 deaths the platform share rose in 61 countries and fell in 21 (median +1.8 percentage points), with the largest increases in South Africa (+8.1) and Lesotho (+8.0). Conclusions Whether vaccines or platforms come first is an empirical country attribute, not a global verdict. The 204-country typology and accompanying dataset offer a concrete starting point for allocating the next increment of child pneumonia resources.

Abstract: Objectives: Tuberculosis (TB) in children is preventable and curable yet weakly diagnosed, notified, and monitored only to age 14 years. We analyzed the 0–19-year TB burden in the Global Burden of Disease Study (GBD) 2023. Methods: We aggregated deaths and incident cases (95% uncertainty intervals [UIs]), 1990–2023, for four age bands across 204 countries, 21 regions and five Socio-demographic Index (SDI) quintiles; computed trends, pandemic-window changes with Monte Carlo–propagated uncertainty, and fixed-2021 SDI gradients, benchmarking against WHO estimates and End TB 2025 milestones. Results: In 2023, TB caused 87,764 deaths (95% UI 65,765–109,764) at ages 0–19 years—about 240 daily—and 1,665,272 incident cases; deaths fell 65.5% since 1990. Low- plus low-middle-SDI countries carried 90.3% of deaths across a 531-fold mortality gradient. GBD 0–14-year mortality was 39.9% of the like-for-like WHO estimate (66,146 vs 166,000); incidence agreed closely (80.8%). Deaths fell 23.9% over 2015–2023 against the 75% milestone. Adolescents aged 15–19 years improved slowest. Conclusions: Measurement systems disagree 2.5-fold on pediatric TB deaths, milestones are off track three-fold, and the burden concentrates where monitoring is weakest. Reconciling estimation, extending monitoring to ages 15–19 years, and concentrating resources on high-burden countries are prerequisites for ending TB in children.