We present a rare case of multicentric Castleman disease (MCD) complicated by severe respiratory failure, which was successfully managed through bilateral lung transplantation. A 31-year-old male patient exhibited progressive dyspnea attributed to MCD associated with bronchiolitis obliterans. Pretransplant evaluations indicated severe hypercapnia and markedly impaired pulmonary function. Despite the administration of steroid therapy, the patient's respiratory status continued to decline. Consequently, he underwent bilateral lung transplantation, which resulted in significant alleviation of hypercapnia and considerable improvement in pulmonary function. Four years posttransplant, the patient remains alive and does not require supplemental oxygen. This case highlights the potential efficacy of bilateral lung transplantation in addressing severe respiratory complications associated with MCD.

OBJECTIVES:This study develops a visual scoring system based on chest computed tomography (CT) findings to assess donor lung function and explores its use for brain-dead donors. METHODS:We conducted a retrospective cohort study of 151 donors after brain death managed by our local Organ Procurement Organization from January 1 to June 30, 2024. A multidisciplinary team developed a chest CT evaluation protocol based on Fleischner Society guidelines. Lung lesions were scored lobe-by-lobe for statistical analysis. RESULTS:Of 151 potential donors, 56 (37.09%) underwent lung transplantation. Transplanted lungs had a higher proportion of blood type O, better oxygenation index, lower C-reactive protein and procalcitonin level, and lower CT scores compared to non-transplanted lungs. A higher total lung score (TLS) was strongly and negatively associated with lung utilization (OR 0.643, P < .001). ROC curve analysis indicated good discriminative ability for the TLS alone (AUC = 0.803). Our findings establish that chest CT visual scoring is a valuable univariable tool for assessing lungs from brain-dead donors. Based on the CT scoring results, the overall utilization rate of potential lung lobes reached 79.22%. CONCLUSIONS:In the evaluation of donor lungs, a high TLS demonstrates a significant negative univariable association with lung utilization rates and exhibits good univariable diagnostic accuracy. The TLS has the potential to serve as a powerful and practical screening tool for donor lung assessment. Our findings suggest that chest CT visual scoring holds potential importance in assessing lungs from brain-dead donors and provides meaningful insights into the evaluation of donor lung lobes. However, further studies with larger sample sizes are required to explore these findings in greater depth.

INTRODUCTION:Endoplasmic reticulum (ER) stress and oxidative stress are closely linked in driving the TGF-β1-mediated proliferation and myofibroblast differentiation of lung fibroblasts during pulmonary fibrosis. Silibinin (SIL), a bioactive compound derived from Silybum marianum l., has been proven to suppress inflammatory responses in a bleomycin (BLM) mouse model, but the protective mechanisms and specific molecular target through which SIL acts in pulmonary fibrosis remain unclear. OBJECTIVES:This study aimed to identify the direct molecular target of SIL, and investigate the mechanisms by which SIL exerts its anti-fibrotic effect. METHODS:A mouse model of BLM-induced pulmonary fibrosis and a cellular model of TGF-β1-induced fibroblast activation were utilized to explore the mechanism by which SIL inhibits fibroblast functions. Limited proteolysis-mass spectrometry (LiP-MS) technology, molecular docking and surface plasmon resonance (SPR) were used to identify the molecular target of SIL. RESULTS:SIL treatment significantly attenuated BLM-induced pulmonary fibrosis in mice by suppressing both the proliferation and differentiation of lung fibroblasts. SIL also reduced BLM-induced ER stress and oxidative stress in mouse lung fibroblasts. In vitro, SIL markedly inhibited TGF-β1-induced fibroblast proliferation, myofibroblast differentiation, and extracellular matrix (ECM) deposition by attenuating ER stress and oxidative stress in primary normal human lung fibroblasts (NHLFs), IPF-derived lung fibroblasts (IPF-HLFs), and the MRC-5 cell line. Using an integrated approach combining LIP-MS, molecular docking, and SPR, we identified Annexin A6 (ANXA6) as the direct molecular target of SIL. ANXA6 knockdown in lung fibroblasts reduced TGF-β1-induced ROS accumulation, ER stress, and subsequent fibroblast activation, whereas ANXA6 overexpression exacerbated these effects. Mechanistically, SIL bound to ANXA6, leading to inactivation of the PI3K/AKT/mTOR signaling and thereby alleviating fibroblast activation. CONCLUSION:Our finding identifies ANXA6 as a promising therapeutic target for pulmonary fibrosis and proposes SIL as its natural inhibitor, thereby providing crucial mechanistic insights for developing ANXA6-targeted therapies against IPF.

OBJECTIVES:The impact of donor-recipient age difference on survival after lung transplantation (LTx) remains unclear. This study investigates effects in different recipient age groups to optimize donor-recipient matching. METHODS:Analysing United Network for Organ Sharing (UNOS) data (2005-2015), we stratified adult first-time LTx recipients into 3 age strata (18-40, 40-60, 60-80 years). Donor-recipient age difference (Δ = donor age-recipient age) was classified into Δ  <  0 and Δ ≥ 0 groups; the 60-80 stratum was further divided into Δ < -10 and Δ  <  0 to ≤ -10 groups. Outcomes included 5-year (primary) and 10-year patient and graft survival, with subgroup analyses by underlying pulmonary disease. RESULTS:Δ  <  0 was associated with significantly better 5-year graft survival in the 18-40 and 40-60 strata (adjusted hazard ratio [HR]: 1.21 [1.02-1.44], P = .031 in 18-40; 1.19 [1.05-1.35], P = .006 in 40-60). Among recipients aged 60-80 (Δ < 0 only), Δ<-10 showed superior 5-year patient survival compared to Δ  <  0 to ≤ -10 (adjusted HR 1.23 [1.10-1.37], P < .001). Secondary analyses showed in 40-60, Δ < 0 had better 10-year patient survival (adjusted HR: 1.14 [1.02-1.27], P = .017); and in 60-80, Δ<-10 remained favourable (adjusted HR: 1.12 [1.02-1.23], P = .015). Subgroup analyses confirmed greater benefit younger donors in cystic fibrosis recipients aged 18-40 and 40-60, and idiopathic pulmonary fibrosis recipients aged 60-80. CONCLUSIONS:Younger donors correlate with better intermediate- and long-term post-transplant survival, particularly for graft survival, supporting individualized preferential matching when clinically feasible.

Background:Heart-lung transplantation is a critical intervention for pediatric end-stage cardiopulmonary diseases, including severe pulmonary hypertension. Post-transplant rejection, predominantly pulmonary, poses significant challenges. Tubeless spontaneous ventilation is an emerging anesthetic modality that improves prognosis by minimizing the risk of mechanical ventilation. Case Description:This case report details a 15-year-old male patient who met the indications for combined heart-lung transplantation due to severe pulmonary hypertension in combination with right heart failure. The patient underwent combined heart-lung transplantation under tubeless spontaneous ventilation anesthesia. On postoperative day 6, the patient was observed to have early signs of pulmonary rejection, which was confirmed by testing for non-human leukocyte antigen antibodies. A tailored immunosuppressive regimen, including mycophenolate mofetil, methylprednisolone, and tacrolimus, was initiated. The patient also received antimicrobial treatment, along with nutritional support. On postoperative day 15, chylothorax was diagnosed, which was managed through fasting and modification of antifungal therapy due to hepatic dysfunction. Furthermore, exercise rehabilitation constitutes a significant component of the treatment regimen that patients receive. A phased rehabilitation program is a structured, multifaceted approach to recovery that encompasses all aspects of the patient's hospitalization. It incorporates active and passive physical activities, postural and endurance training, respiratory muscle training, and other exercises, all meticulously designed to address the patient's specific needs and facilitate their recovery. The patient exhibited a marked recovery in clinical symptoms by day 23 and was subsequently discharged from the hospital. Conclusions:Tubeless anesthesia has been demonstrated to expedite postoperative recovery and mitigate pulmonary complications. Early rejection detection, tailored immunosuppression, and multidisciplinary coordination were instrumental in overcoming challenges. This case underscores the potential to reduce morbidity and highlights integrative strategies for optimizing transplant outcomes in children, emphasizing personalized care and vigilant monitoring.

Genetically engineered pig lungs have not previously been transplanted into humans, leaving key questions unanswered regarding the human immune response in the context of a xenotransplanted lung and the possibility of hyperacute rejection. Here, we report a case of pig-to-human lung xenotransplantation, in which a lung from a six-gene-edited pig was transplanted into a 39-year-old brain-dead male human recipient following a brain hemorrhage. The lung xenograft maintained viability and functionality over the course of the 216 hours of the monitoring period, without signs of hyperacute rejection or infection. Severe edema resembling primary graft dysfunction was observed at 24 hours after transplantation, potentially due to ischemia-reperfusion injury. Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9. Immunosuppression included rabbit anti-thymocyte globulin, basiliximab, rituximab, eculizumab, tofacitinib, tacrolimus, mycophenolate mofetil and tapering steroids, with adjustments made during the postoperative period based on assessments of immune status. Although this study demonstrates the feasibility of pig-to-human lung xenotransplantation, substantial challenges relating to organ rejection and infection remain, and further preclinical studies are necessary before clinical translation of this procedure.

Background:De novo post-transplant malignancy (PTM) is a significant complication after transplantation. Limited research exists on the incidence rates in recent lung transplant recipients (LTRs). This study aims to determine the risk spectrum of malignancies in LTRs and analyze their temporal evolution. Methods:Data on 32,480 LTRs were extracted from the United States (U.S.) Organ Procurement Transplant Network/United Network for Organ Sharing (UNOS) database. We described the annual incidence rates and calculated the standardized incidence ratio (SIR). Results:Among the 32,480 LTRs, the cancer incidence rate was 23.11%. The incidence of malignancies varied over time, initially increasing and then stabilizing in the first 10 years post-transplant. The overall incidence of cancers excluding non-melanoma skin cancer (NMSC) remained stable, with some tumors linked to viral infections being more common early on. Older age at transplantation and male gender were associated with higher cancer incidence risk. Besides cutaneous squamous cell carcinoma (cSCC) (n=3,706) and basal cell carcinoma (BCC) (n=1,054), the most common malignancies were lung cancer [n=580; incidence rate 455.55 per 100,000 person-years (PY); SIR =4.088] and non-Hodgkin lymphoma (NHL) (n=578; incidence rate 453.98 per 100,000 PY; SIR =13.266). Conclusions:LTRs have a higher cancer risk compared to the general population. Targeted monitoring based on PTM occurrence patterns is necessary to prevent and detect tumors early. These findings assist in identifying high cancer incidence periods and guide predictions of tumor development.

Severe respiratory viral infections lead to extensive damage to the alveolar epithelium and also induce a robust immune response. How the immune microenvironment interacts with lung stem/progenitor cells and impacts alveolar regeneration is poorly understood. Here, we found that dysplastic KRT5+ basal-like cells, which emerge after severe viral infections, contribute to the recruitment and sequestration of CD4+ effector and CD8+ T cells in the lung after viral clearance in a CXCR3- and integrin α4β7-dependent manner. Persistent CD4+ effector and CD8+ T cells impair alveolar regeneration mediated via airway secretory cells by secreting IFNγ, thereby inhibiting lung functional repair. Importantly, anti-IFNγ treatment improves alveolar regeneration and lung function in vivo. Overall, our study reveals the pathogenetic role of dysplastic KRT5+ cells in alveolar regeneration, serving as a niche for tissue-resident lymphocytes that specifically inhibit alveolar regeneration. Additionally, our findings provide a potential therapeutic strategy to improve alveolar regeneration after viral pneumonia.

Objective Awake extracorporeal membrane oxygenation (ECMO) This serves as an effective bridge to lung transplantation (LTx). This study evaluated the feasibility and safety of awake ECMO for operating room (OR) extubation following LTx to minimize lung injury caused by mechanical ventilation (MV). Design and method Patients who underwent LTx with postoperative non-awake or awake veno-arterial (VA)-ECMO at our center were included and matched by propensity score. Clinical characteristics and surgical procedures of the awake VA-ECMO cases were detailed, and perioperative outcomes were compared between groups. Results and conclusions Results: Twenty-two patients were included in each of the awake-VA-ECMO and non-awake-VA-ECMO groups. Intraoperatively, hemodynamics were comparable between groups (P>0.05), whereas the awake-VA-ECMO group exhibited a lower respiratory rate (15 vs. 16 breaths/min, P=0.009) and better lung compliance (45 vs. 20, P<0.001). Postoperatively, patients in the awake-VA-ECMO group had shorter durations of invasive MV (0 vs. 10 days, P=0.029), intensive care unit (ICU) stay (7 vs. 18 days, P=0.018), postoperative hospital stay (20 vs. 39 days, P=0.011), and total hospital stay (28 vs. 44 days, P=0.035), as well as more favorable laboratory profiles, including higher intraoperative albumin (P=0.004) and lower preoperative lactic acid (P=0.021). Furthermore, the awake-VA-ECMO group had lower hospitalization costs (422,122 vs. 565,883, P=0.014). Despite these findings, in-hospital mortality, the incidence of re-intubation and complications, as well as postoperative 3-month survival, were comparable between groups (P>0.05).Conclusions: Awake VA-ECMO is feasible and safe for OR extubation following LTx and may reduce the patients’ need for postoperative invasive MV in the ICU.

BACKGROUND:High-flow nasal cannula (HFNC) oxygen therapy is widely used primarily for preoxygenation and postextubation respiratory support. However, its intraoperative application remains uncommon. This study evaluated the effects of the HFNC on respiratory mechanics and hemodynamics in thoracoscopic surgery under spontaneous ventilation. METHODS:This randomized trial included 165 patients scheduled for thoracoscopic surgery from 2023 to 2024. Patients were assigned to 3 ventilation supports: double-lumen endotracheal tube (intubation group, n = 55), laryngeal mask airway group (n = 55), or HFNC (n = 55). Intraoperative respiratory and hemodynamic changes, postoperative recovery, and adverse effects were analyzed. RESULTS:The oxygenation index was comparable intraoperatively but higher in the HFNC group 5 minutes after extubation (P = .018). Intraoperative carbon dioxide was higher in the HFNC and laryngeal mask airway groups (P < .05) but gradually normalized postoperatively. The HFNC shortened extubation time (30 vs 33 vs 37 minutes; P = .005) and postoperative anesthesia care unit stay (70 vs 75 vs 85 minutes; P < .001) and reduced the incidence of nausea, sore throat, and dizziness in the 24 hours postoperatively (P = .005, P = .001, P = .002). HFNC patients demonstrated improved early mobility and nocturnal sleep and lower numeric pain rating scale score at rest and during activity (P < .05). Propofol and opioid use was lower in the HFNC group (P = .016, P < .001), whereas dexmedetomidine consumption was higher (P = .002). CONCLUSIONS:The HFNC provides a stable form of anesthesia compared with laryngeal mask and intubation and is associated with early improved rehabilitation in thoracoscopic surgery.

Emerging evidence suggests that minimal residual disease (MRD) monitoring in solid tumors has implications for prognosis, treatment response, and therapeutic intervention. However, detecting MRD requires highly sensitive and specific circulating tumor DNA (ctDNA) assays. Therefore, we developed an innovative MRD monitoring assay that offers superior performance and cost advantage. Our approach utilizes a comprehensive genomic profiling panel to characterize the patient-specific mutational landscape of tumor tissue and selects up to 20 top-ranked variants to design a personalized panel, which is integrated with a tumor-naive cancer-type-specific fixed panel for ultra-deep sequencing of plasma ctDNA to monitor MRD in common solid tumors. Its limit of detection at the sample level reaches as low as 0.005%, with a specificity of 100%. Furthermore, when applied to colorectal, breast, and lung cancer patients, the ctDNA-MRD assay accurately predicted postoperative recurrence, prior to radiographic imaging by a median of 112 days for breast cancer and 83 days for lung cancer. In the tracked variants, clonal mutations demonstrated superior prognostic value compared to subclonal variants. This personalized MRD monitoring assay has the potential to enhance early detection of residual or recurrent disease, enable patient prognostic stratification, and inform clinical decision-making for patients with common solid tumors.

Background:Pre-transplant malignancy (PTM) is a relative contraindication for lung transplantation (LTx). The proportion of patients with PTM in LTx is increasing annually. We sought to identify modifiable risk factors affecting patient survival and evaluate the prognosis of different types of PTM. Methods:We retrospectively reviewed primary adult lung transplantation recipients (LTR) in the United Network for Organ Sharing (UNOS) registry. Primary stratification was performed by PTM and secondary stratification by tumor type. Kaplan-Meier survival analysis was used to estimate survival and Cox proportional hazards model was used to assess risk factors. Results:Compared to patients without PTM, patients with PTM exhibit a significantly higher mortality rate starting 1 year post-transplantation (1-year: P=0.02; 3-, 5-, 10-year: P<0.001). Multivariate Cox regression analysis identified age, male sex, single LTx, and high lung allocation score (LAS) as independent risk factors for 5-year mortality in PTM patients. After stratifying PTM, lung PTM was an independent risk factor for death at all periods after transplantation (1-year: P<0.001; 3-year: P=0.001; 5-year: P=0.002; 10-year: P=0.005), and leukemia PTM significantly impacted medium- and long-term mortality (3-year: P=0.03; 5-year: P=0.01; 10-year: P=0.004). Additionally, cutaneous melanoma and genitourinary PTM were associated with long-term mortality. Skin cancer, lung cancer and leukemia were significantly associated with cancer-specific mortality (P<0.05). Conclusions:The prognosis of patients with PTM after LTx is worse than that of patients without PTM. When focusing on long-term survival, patients with a history of lung cancer, leukemia, melanoma and genitourinary system malignant tumors require more careful selection.

Human coronaviruses (CoV) cause respiratory infections that range from mild to severe. CoVs are a large family of viruses with considerable genetic heterogeneity and a multitude of viral types, making preventing and treating these viruses difficult. Comprehensive treatments that inhibit CoV infections fulfill a pressing medical need and may be immensely valuable in managing emerging and endemic CoV infections. As the main protease (Mpro) is highly conserved across many CoVs, this protease has been identified as a route for broad CoV inhibition. We utilize the advanced generative chemistry platform Chemistry42 for de novo molecular design and obtained novel small-molecule, non-peptide-like inhibitors targeting the SARS-CoV-2 Mpro. ISM3312 is identified as an irreversible, covalent Mpro inhibitor from extensive virtual screening and structure-based optimization efforts. ISM3312 exhibits low off-target risk and outstanding antiviral activity against multiple human coronaviruses, including SARS-CoV-2, MERS-CoV, 229E, OC43, NL63, and HKU1 independent of P-glycoprotein (P-gp) inhibition. Furthermore, ISM3312 shows significant inhibitory effects against Nirmatrelvir-resistant Mpro mutants, suggesting ISM3312 may contribute to reduced viral escape in these settings. Incorporating ISM3312 and Nirmatrelvir into antiviral strategy could improve preparedness and reinforce defenses against future coronavirus threats.

INTRODUCTION:Family caregivers play an indispensable role in the care of solid organ transplant patients, undertaking a wide range of tasks from basic daily care to complex medical management. However, these responsibilities come with substantial challenges, placing additional strain on caregivers who bear significant physical, emotional, financial and social burdens, along with numerous unmet support needs. Currently, the exploration of challenges and support needs among family caregivers in the caregiving process is limited to primary research, lacking a synthesised and comprehensive understanding of the issues. Therefore, the aim of this scoping review is to summarise the available evidence to accentuate the diverse challenges encountered by family caregivers and to identify their specific supportive needs, while also pinpointing the areas of research that have yet to be explored. METHODS AND ANALYSIS:Following the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews, this review will be conducted. The initial search of PubMed to identify keywords was conducted on 16 November 2024. Additionally, Web of Science Core Collection, ProQuest, Scopus, CINAHL (EBSCOhost), China National Knowledge Infrastructure (CNKI) and China Wan Fang database will be systematically searched for relevant literature. No language or date restrictions will be applied. Two reviewers will independently screen the articles based on title, abstract and full text. Data extraction and analysis of results will be presented in tables or graphs. ETHICS AND DISSEMINATION:Ethical approval is not necessary for this scoping review. The study findings will be published in open-access journals after peer review. These findings will provide information for healthcare providers to alleviate the plight of family caregivers and to pave the way forward towards more resilient caregiver support systems.

OBJECTIVES:Amid donor shortages, chest X-ray (CXR) is widely used for lung donor screening due to its accessibility, low cost, and rapid imaging. We evaluated the impact of donor CXR infiltrates on post-transplant survival to inform donor lung utilization. METHODS:This retrospective cohort study included adult lung transplant recipients from the United Network for Organ Sharing (UNOS) registry from May 5, 2005 to December 31, 2022. Patients were grouped by the presence or absence of donor CXR infiltrates. Using propensity score matching (PSM) to control variable balance, Kaplan-Meier survival analysis estimated post-transplant survival (at 30 days, 90 days, 1 year, 5 years, and 10 years). Multivariable logistic regression models were applied to identify independent risk donor factors of CXR infiltration. RESULTS:Unadjusted analyses showed higher short-term survival (30-day/90-day/1-year) in the presence of chest X-ray infiltration group (PCIG) versus the absence of chest X-ray infiltration group (ACIG) (all P < .05), but no differences in 5-year/10-year survival (P > .05) or median survival (P = .567). After PSM, the 2 groups had similar recipient causes of death and rates of postoperative complications. Obesity, prior pulmonary infection, ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2)<300 mmHg, and positive bronchoscopy independently predicted donor infiltrates (all P < .001). CONCLUSIONS:Mild-to-moderate donor lung CXR infiltrates do not independently impair long-term survival or increase major complications. These findings support rational utilization of such lungs within standardized multivariable assessment.