Hydroalkylation of styrenes enabled by boryl radical mediated halogen atom transfer.

In this study, we present an inexpensive, stable, and easily available boryl radical source (BPh4Na) employed in a Halogen Atom Transfer (XAT) methodology. This mild and convenient strategy unlocks the use of not only alkyl iodides as radical precursors but also of the more challenging alkyl and aryl bromides to generate C-centered radicals. The generated radicals were further engaged in the anti-Markovnikov hydroalkylation of electronically diverse styrenes, therefore achieving the formation of C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. A series of experimental and computational studies revealed the prominent role of BPh4Na in the halogen abstraction step.

Evaluating the efficacy and safety of letermovir compared to valganciclovir for the prevention of human cytomegalovirus disease in adult lung transplant recipients.

BACKGROUND: Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. METHODS: This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. RESULTS: A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p = .370). The median (interquartile range) white blood cell (WBC) count was 3.1 (2.1-5.6) at LET initiation which increased to 5.1 (3.9-7.2) at the end of follow-up (p <.001). For VGCV controls, WBC was 4.8 (3.4-7.2) at baseline and 5.4 (3.6-7.2) at the end of follow-up; this difference was not statistically significant (p = .395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). CONCLUSION: LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.

Shining light on tryptamine-derived isocyanides: access to constrained spirocylic scaffolds.

Dearomatization of indoles through a charge transfer complex constitutes a powerful tool for synthesizing three-dimensional constrained structures. However, the implementation of this strategy for the dearomatization of tryptamine-derived isocyanides to generate spirocyclic scaffolds remains underdeveloped. In this work, we have demonstrated the ability of tryptamine-derived isocyanides to form aggregates at higher concentration, enabling a single electron transfer step to generate carbon-based-radical intermediates. Optical, HRMS and computational studies have elucidated key aspects associated with the photophysical properties of tryptamine-derived isocyanides. The developed protocol is operationally simple, robust and demonstrates a novel approach to generate conformationally constrained spirocyclic scaffolds, compounds with high demand in various fields, including drug discovery.

The crucial role of stability of intercalating agent for DNA binding studies in DMSO/water system.

In recent years, extensive research has been directed towards understanding the interactions between various zinc complexes with DNA, specifically delving into their intercalation and binding behaviors. The binding of zinc complexes to DNA is particularly intriguing due to their distinctive intercalating capabilities. This study unveils a remarkable phenomenon observed with a specific Zn complex, ([B-Zn-N3], where B is a Schiff base ligand), during DNA intercalation investigations in the popular DMSO-Water binary solvent mixture. An unanticipated observation revealed time-dependent changes in the UV-visible absorption spectroscopic studies, coupled with the existence of an isosbestic point. This observation questions the stability of the intercalating agent itself during the intercalation process. The emergence of a decomposed product during the intercalation study has been confirmed through various analytical techniques, including CHN analysis, MALDI mass, XPS, Raman spectroscopy, and Powder XRD. The change in the chemical species on intercalation is further substantiated by theoretical studies, adding depth to our understanding of the intricate dynamics at play during DNA intercalation with the [B-Zn-N3] complex in the DMSO-Water system.

Cell-type-specific and disease-associated expression quantitative trait loci in the human lung.

Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis. Defining the genetic control of gene expression in a cell-type-specific and context-dependent manner is critical for understanding the mechanisms through which genetic variation influences complex traits and disease pathobiology. To this end, we performed single-cell RNA sequencing of lung tissue from 66 individuals with pulmonary fibrosis and 48 unaffected donors. Using a pseudobulk approach, we mapped expression quantitative trait loci (eQTLs) across 38 cell types, observing both shared and cell-type-specific regulatory effects. Furthermore, we identified disease interaction eQTLs and demonstrated that this class of associations is more likely to be cell-type-specific and linked to cellular dysregulation in pulmonary fibrosis. Finally, we connected lung disease risk variants to their regulatory targets in disease-relevant cell types. These results indicate that cellular context determines the impact of genetic variation on gene expression and implicates context-specific eQTLs as key regulators of lung homeostasis and disease.

Late-Onset Exudative Pleural Effusions Without Concomitant Airway Obstruction or Lung Parenchymal Abnormalities: A Novel Presentation of Chronic Lung Allograft Dysfunction.

Restrictive allograft syndrome (RAS) is an aggressive variant of CLAD characterized by progressive restrictive ventilatory decline and persistent pleuro-parenchymal changes that can be seen on chest CT. We identified four lung transplant recipients with a progressive restrictive ventilatory defect due to lymphocyte-predominant exudative pleural effusions, but no pleuro-parenchymal abnormalities typical of RAS. Using molecular analysis, we also found increased levels of previously described immune markers of RAS, including NFkB, 20S proteasome, lipocalin, TNFα, and TGFß, within the circulating small extracellular vesicles of the remaining living lung transplant recipient. Despite the absence of lung parenchymal changes, these patients had a poor prognosis with rapid deterioration in allograft function and no response to pleural-based interventions such as thoracentesis, decortication, and pleurodesis. We hypothesize that these cases represent a distinct CLAD phenotype characterized by progressive restriction due to pleural inflammation, lymphocyte-predominant pleural effusion, resultant compressive atelectasis, and eventual respiratory failure in the absence of lung parenchymal involvement.

Efficient, narrow-band, and stable electroluminescence from organoboron-nitrogen-carbonyl emitter.

Organic light-emitting diodes (OLEDs) exploiting simple binary emissive layers (EMLs) blending only emitters and hosts have natural advantages in low-cost commercialization. However, previously reported OLEDs based on binary EMLs hardly simultaneously achieved desired comprehensive performances, e.g., high efficiency, low efficiency roll-off, narrow emission bands, and high operation stability. Here, we report a molecular-design strategy. Such a strategy leads to a fast reverse intersystem crossing rate in our designed emitter h-BNCO-1 of 1.79×105 s-1. An OLED exploiting a binary EML with h-BNCO-1 achieves ultrapure emission, a maximum external quantum efficiency of over 40% and a mild roll-off of 14% at 1000 cd·m-2. Moreover, h-BNCO-1 also exhibits promising operational stability in an alternative OLED exploiting a compact binary EML (the lifetime reaching 95% of the initial luminance at 1000 cd m-2 is ~ 137 h). Here, our work has thus provided a molecular-design strategy for OLEDs with promising comprehensive performance.

Evolving impact of the COVID-19 pandemic on lung transplant recipients: A single-center experience.

BACKGROUND: Lung transplant recipients (LTRs) are at increased risk of morbidity and mortality from coronavirus disease 2019 (COVID-19); however, the disease course has changed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants have mutated. We compared COVID-19-related clinical outcomes in LTRs at different stages of the pandemic. We also identified risk factors for developing severe COVID-19 independent of the dominant SARS-CoV-2 variant. METHODS: This single-center, retrospective cohort study of LTRs with COVID-19 used Cox regression analyses and bootstrapping to identify factors affecting COVID-19 severity. RESULTS: Between March 2020 and August 2022, 195 LTRs were diagnosed with COVID-19, almost half (89 [45.6%]) during the Omicron period. A total of 113 (58.5%) LTRs were hospitalized and 47 (24.1%) died. Age >65 years increased the risk of hospitalization and death. Although infection with the Omicron variant was associated with a lower risk of hospitalization, the median length of hospital stay (10 days, [interquartile range, 5-19]) was similar between the variants. Intensive care unit (ICU) admission and death were more common with the Delta variant but comparable between the original, Alpha, and Omicron variants. Remdesivir and molnupiravir reduced the risk of hospitalization, and monoclonal antibody therapy reduced the risk of ICU admission, intubation, and death. Vaccination and pre-exposure prophylaxis (PrEP) with tixagevimab-cilgavimab did not significantly reduce COVID-19-related ICU admission, intubation, or mortality among LTRs. CONCLUSIONS: LTRs with COVID-19 continue to have high hospitalization rates and prolonged hospital stays, despite the reduced virulence of the Omicron variant. More effective PrEP and therapeutic interventions for COVID-19 among vulnerable patient groups are needed.

Immune responses of lung transplant recipients against SARS-CoV-2 and common respiratory coronaviruses: Evidence for pre-existing cross-reactive immunity.

Humoral and cellular immune responses to SARS-CoV-2 and other coronaviruses in lung transplant recipients are unknown. We measured antibodies and T cell responses against the SARS-CoV-2 spike S2 and nucleocapsid antigens and spike antigens from common respiratory coronaviruses (229E, NL63, OC43, and HKU1) after vaccination or infection of LTxRs. 148 LTxRs from single center were included in this study: 98 after vaccination and 50 following SARS-CoV-2 infection. Antibodies were quantified by enzyme-linked immunosorbent assay. The frequency of T cells secreting IL2, IL4, IL10, IL17, TNFα, and IFNγ were enumerated by enzyme-linked immunospot assay. Our results have shown the development of antibodies to SARS-CoV-2 spike protein in infected LTxRs (39/50) and vaccinated LTxRs (52/98). Vaccinated LTxRs had higher number of T cells producing TNFα but less cells producing IFNγ than infected LTxRs in response to the nucleocapsid antigen and other coronavirus spike antigens. We didn't find correlation between the development of antibodies and cellular immune responses against the SARS-CoV-2 spike protein after vaccination. Instead, LTxRs have pre-existing cellular immunity to common respiratory coronaviruses, leading to cross-reactive immunity against SARS-CoV-2 which likely will provide protection against SARS-Cov-2 infection.

Prior SARS-CoV-2 infection may not alter the clinical course of COVID-19 in lung transplant recipients: A single-center experience.

BACKGROUND: In the general population, prior infection with SARS-CoV-2 reduces the risk of severe COVID-19; however, studies in lung transplant recipients (LTRs) are lacking. We sought to describe the clinical course of COVID-19 recurrence and compare outcomes between the first and second episodes of COVID-19 in LTRs. METHODS: We conducted a retrospective, single-center cohort study of LTRs with COVID-19 between January 1, 2022, and September 30, 2022, during the Omicron wave. We compared the clinical course of a second episode of COVID-19 to that of the patients' own first episode and to that of LTRs who developed a first episode during the study period. RESULTS: During the study period, we identified 24 LTRs with COVID-19 recurrence and another 75 LTRs with a first episode of COVID-19. LTRs who survived the initial episode of COVID-19 had a similar disease course with recurrence, with a trend toward reduced hospitalization (10 (41.6%) vs. 4 (16.7%), p = .114). Furthermore, compared to LTRs with a primary infection during the Omicron wave, those with a reinfection had a non-statistically significant trend toward reduced hospitalizations (aOR .391, 95% CI [.115-1.321], p = .131), shorter lengths-of-stay (median, 4 vs. 9 days, p = .181), and reduced intensive care unit admissions, intubations, and COVID-19-related mortality. CONCLUSIONS: LTRs who survive the first episode of COVID-19 are likely to have a similar clinical course with recurrent episodes. Although recurrent COVID-19 may be milder, larger, well-powered studies are needed to confirm this observation. Ongoing precautions are warranted.

Pre-exposure Prophylaxis with Tixagevimab-cilgavimab did not Reduce Severity of COVID-19 in Lung Transplant Recipients with Breakthrough Infection.

Lung transplant recipients (LTRs) have an increased risk of COVID-19-related morbidity and mortality. Tixagevimab-cilgavimab (tix-cil) is a long-acting monoclonal antibody combination granted Emergency Use Authorization approval by the US Food and Drug Administration for COVID-19 pre-exposure prophylaxis (PrEP) in immunocompromised patients. We sought to determine whether tix-cil 300-300 mg reduced the incidence and disease severity of severe acute respiratory syndrome coronavirus 2 infection in LTRs during the Omicron wave. Methods: We performed a retrospective, single-center cohort study of LTRs who had received a COVID-19 diagnosis between December 2021 and August 2022. We compared baseline characteristics and clinical outcomes after COVID-19 between LTRs who received tix-cil PrEP and those who did not. We then conducted propensity-score matching based on baseline characteristics and therapeutic interventions and compared clinical outcomes between the 2 groups. Results: Of 203 LTRs who received tix-cil PrEP and 343 who did not, 24 (11.8%) and 57 (16.6%), respectively, developed symptomatic COVID-19 (hazard ratio [HR], 0.669; 95% confidence interval [CI], 0.415-1.079; P = 0.099). The hospitalization rate of LTRs with COVID-19 during the Omicron wave trended lower in the tix-cil group than in the non-tix-cil group (20.8% versus 43.1%; HR, 0.430; 95% CI, 0.165-1.118; P = 0.083). In propensity-matched analyses, 17 LTRs who received tix-cil and 17 LTRs who did not had similar rates of hospitalization (HR, 0.468; 95% CI, 0.156-1.402; P = 0.175), intensive care unit admission (HR, 3.096; 95% CI, 0.322-29.771; P = 0.328), mechanical ventilation (HR, 1.958; 95% CI, 0.177-21.596; P = 0.583), and survival (HR, 1.015; 95% CI, 0.143-7.209; P = 0.988). COVID-19-related mortality was high in both propensity-score-matched groups (11.8%). Conclusions: Breakthrough COVID-19 was common among LTRs despite tix-cil PrEP, possibly due to reduced efficacy of monoclonal antibodies against the Omicron variant. Tix-cil PrEP may reduce the incidence of COVID-19 in LTRs, but it did not reduce disease severity during the Omicron wave.

Cell type-specific and disease-associated eQTL in the human lung.

Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis (PF). Defining the genetic control of gene expression in a cell-type-specific and context-dependent manner is critical for understanding the mechanisms through which genetic variation influences complex traits and disease pathobiology. To this end, we performed single-cell RNA-sequencing of lung tissue from 67 PF and 49 unaffected donors. Employing a pseudo-bulk approach, we mapped expression quantitative trait loci (eQTL) across 38 cell types, observing both shared and cell type-specific regulatory effects. Further, we identified disease-interaction eQTL and demonstrated that this class of associations is more likely to be cell-type specific and linked to cellular dysregulation in PF. Finally, we connected PF risk variants to their regulatory targets in disease-relevant cell types. These results indicate that cellular context determines the impact of genetic variation on gene expression, and implicates context-specific eQTL as key regulators of lung homeostasis and disease.

A randomized controlled trial of presatovir for respiratory syncytial virus after lung transplant.

BACKGROUND: Respiratory syncytial virus (RSV) infection in lung transplant recipients is associated with high morbidity. This study evaluated the RSV fusion inhibitor presatovir in RSV-infected lung transplant recipients. METHODS: In this international Phase 2b, randomized, double-blind, placebo-controlled trial (NCT02534350), adult lung transplant recipients with symptomatic confirmed RSV infection for ≤7 days received oral presatovir 200 mg on day 1 and 100 mg daily on days 2 to 14, or placebo (2:1), with follow-up through day 28. There were 2 coprimary endpoints: time-weighted average change in nasal RSV load from day 1 to 7, calculated from nasal swabs, in the full analysis set ([FAS]; all patients who received study drug and had quantifiable baseline nasal RSV load) and time-weighted average change in nasal RSV load from day 1 to 7 in the subset of patients with pretreatment symptom duration at the median or shorter of the FAS. Secondary endpoints were changes in respiratory infection symptoms assessed using the Influenza Patient-Reported Outcomes questionnaire and lung function measured by spirometry. RESULTS: Sixty-one patients were randomized, 40 received presatovir, 20 placebo, and 54 were included in efficacy analyses. Presatovir did not significantly improve the primary endpoint in the FAS (treatment difference [95% CI], 0.10 [-0.43, 0.63] log10 copies/ml; p = 0.72) or the shorter symptom-duration subgroup (-0.12 [-0.94, 0.69] log10 copies/ml; p = 0.76). Secondary endpoints were not different between presatovir and placebo groups. Presatovir was generally well tolerated. CONCLUSIONS: Presatovir treatment did not significantly improve change in nasal RSV load, symptoms, or lung function in lung transplant recipients.

Antireflux surgery versus medical management of gastro-oesophageal reflux after lung transplantation.

OBJECTIVES: Gastro-oesophageal reflux disease after lung transplantation may be associated with chronic lung allograft dysfunction. Aspiration may continue on medical management of reflux, but antireflux surgery potentially reduces all reflux. We compared outcomes between medical and surgical management of reflux in lung recipients. METHODS: Lung recipients with an elevated DeMeester score (≥14.72) on post-transplant reflux testing between 2015 and 2020 were included. Patients were divided into 2 groups: group A (underwent surgery) and group B (medically managed). Endpoints were pulmonary function, allograft dysfunction-free survival and overall survival. Further analysis included subgroups: A1 (early surgery, <6 months) and A2 (late surgery, >6 months), and B1 (DeMeester <29.9) and B2 (DeMeester ≥30). RESULTS: A total of 186 included subjects were divided into groups A [n = 46 (A1, n = 36; A2, n = 10)] and B [n = 140 (B1, n = 78; B2, n = 62)]. Compared to medically managed patients, patients who underwent surgery had a higher prevalence of hiatal hernia (P < 0.001) and a lower prevalence of oesophageal motility disorders (P = 0.036). Recipients who underwent surgery had superior pulmonary function at 5 years compared to group B (P < 0.05) and longer allograft dysfunction-free survival than subgroup B2 (P = 0.028). Furthermore, early surgery was associated with longer survival than late surgery (P = 0.021). CONCLUSIONS: Antireflux surgery in recipients with reflux improved long-term allograft function, and early surgery showed a survival benefit. Allograft dysfunction-free survival of lung recipients who underwent surgery was significantly better than that of medically managed patients with DeMeester ≥30. We present an algorithm for appropriate selection of candidates for antireflux surgery after lung transplantation.

Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis.

Accumulation of senescent cells contributes to age-related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) regulate many biological processes; however, the functional contributions of IGFBP2 in lung fibrosis remain largely unclear. Here, we report that intranasal delivery of recombinant IGFBP2 protects aged mice from weight loss and demonstrated antifibrotic effects after bleomycin lung injury. Notably, aged human-Igfbp2 transgenic mice reveal reduced senescence and senescent-associated secretory phenotype factors in alveolar epithelial type 2 (AEC2) cells and they ameliorated bleomycin-induced lung fibrosis. Finally, we demonstrate that IGFBP2 expression is significantly suppressed in AEC2 cells isolated from fibrotic lung regions of patients with IPF and/or pulmonary hypertension compared with patients with hypersensitivity pneumonitis and/or chronic obstructive pulmonary disease. Altogether, our study provides insights into how IGFBP2 regulates AEC2-cell-specific senescence and that restoring IGFBP2 levels in fibrotic lungs can prove effective for patients with IPF.

Association Between Antibodies Against Lung Self-Antigens and Gastroesophageal Reflux in Lung Transplant Candidates.

Gastroesophageal reflux (GER) and pretransplant antibodies against lung self-antigens (SAbs) collagen-V and/or k-alpha 1 tubulin are both independently associated with allograft dysfunction after lung transplantation (LTx). The role of GER in inducing lung injury and SAbs is unknown. We aimed to study the association between pre-LTx GER and SAbs. After IRB approval, we retrieved SAb assays conducted between 2015 and 2019 and collected 24 hour GER data for these patients. Patients were divided into 2 groups: no reflux (GER-) and pathologic reflux (GER+) to compare the prevalence of SAbs. Multivariate analysis was used to study the association between GER and SAbs in the whole cohort and in restrictive lung disease (RLD) and obstructive lung disease (OLD) subsets. Proximal esophageal reflux (PER) events ≥5 was considered abnormal. Patients (n = 134; 73 men) were divided into groups: GER- (54.5%, n = 73) and GER+ (45.5%, n = 61). The prevalence of GER was higher in the RLD than in the OLD subset (p < 0.001). The overall prevalence of SAbs was 53.7% (n = 72), higher in the GER+ than the GER- group (65.6% vs 43.8%, p = 0.012), but comparable between RLD and OLD subsets. Overall, SAbs were associated with GER (p = 0.012) and abnormal PER (p = 0.017). GER and abnormal PER increased the odds of SAbs in the RLD subset (OR [95% CI]: 2.825 [1.033-7.725], p = 0.040 and OR [95% CI]: 3.551 [1.271-9.925], p = 0.014, respectively) but not in the OLD subset. LTx candidates have a high prevalence of SAbs, which are significantly associated with GER and abnormal PER in patients with RLD.

Hospitalized patients with irreversible lung injury from COVID-19 have higher morbidity but similar 1-year survival after lung transplant compared to hospitalized patients transplanted for restrictive lung disease.

BACKGROUND: Hospitalized lung transplant (LT) recipients (LTRs) have higher post-LT morbidity and mortality than those who are well enough to wait for transplant at home. Outcomes after LT for COVID-19-associated acute respiratory distress syndrome (CARDS) may be even worse; thus, we compared post-LT outcomes between hospitalized LTRs transplanted for CARDS and those transplanted for restrictive lung disease (RLD). METHODS: Between 2014 and 2021, hospitalized LTRs ≥18 years old with CARDS or RLD were included. Primary and secondary outcomes were 1-year post-LT survival and postoperative morbidity. For each patient in the CARDS group, an analysis of 1-to-1 matched patients from the RLD group was performed using logistic regression modeling. RESULTS: Of 764 LTRs, 163 (21.3%) were hospitalized at the time of LT; 132 met the inclusion criteria: 11 (8.3%) were transplanted for CARDS and 121 (91.7%) for RLD. LTRs with CARDS were younger with longer pre-LT hospitalization stays and higher rates of pretransplant mechanical ventilation, dialysis, and ECMO as a bridge to transplant. A propensity-matched analysis demonstrated comparable rates of intrathoracic adhesions, posttransplant duration of mechanical ventilation, PGD3 at 72 hours, and delayed chest closure. Compared to LTRs with RLD, those with CARDS had significantly longer posttransplant hospital stays and a higher prevalence of ACR ≥A2 and DSA >2000 MFI, but comparable 1-year survival rates. CONCLUSION: Even with careful selection, LT for patients with CARDS was associated with significant morbidity; however, 1-year survival of recipients with CARDS was comparable to that of matched hospitalized recipients with RLD.

Morbidity of antireflux surgery in lung transplant and matched nontransplant cohorts is comparable.

BACKGROUND: Safety data on perioperative outcomes of laparoscopic antireflux surgery (LARS) after lung transplantation (LT) are lacking. We compared the 30-day readmission rate and short-term morbidity after LARS between LT recipients and matched nontransplant (NT) controls. METHODS: Adult patients who underwent LARS between January 1, 2015, and October 31, 2021, were included. The participants were divided into two groups: LT recipients and NT controls. First, we compared 30-day readmission rates after LARS between the LT and NT cohorts. Next, we compared 30-day morbidity after LARS between the LT cohort and a 1-to-2 propensity score-matched NT cohort. RESULTS: A total of 1328 patients (55 LT recipients and 1273 NT controls) were included. The post-LARS 30-day readmission rate was higher in LT recipients than in the overall NT controls (14.5% vs. 2.8%, p < 0.001). Compared to matched NT controls, LT recipients had a lower prevalence of paraesophageal hernia, a smaller median hernia size, and higher peristaltic vigor. Also compared to the matched NT controls, the LT recipients had a lower median operative time but a longer median length of hospital stay. The proportion of patients with a post-LARS event within 30 postoperative days was comparable between the LT and matched NT cohorts (21.8% vs 14.5%, p = 0.24). CONCLUSIONS: Despite a higher perceived risk of comorbidity burden, LT recipients and matched NT controls had similar rates of post-LARS 30-day morbidity at our large-volume center with expertise in transplant and foregut surgery. LARS after LT is safe.

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis.

The human lung is structurally complex, with a diversity of specialized epithelial, stromal and immune cells playing specific functional roles in anatomically distinct locations, and large-scale changes in the structure and cellular makeup of this distal lung is a hallmark of pulmonary fibrosis (PF) and other progressive chronic lung diseases. Single-cell transcriptomic studies have revealed numerous disease-emergent/enriched cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using sub-cellular resolution image-based spatial transcriptomics, we analyzed the gene expression of more than 1 million cells from 19 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell-types, established the cellular and molecular basis of classical PF histopathologic disease features, and identified a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Using machine-learning and trajectory analysis methods to segment and rank airspaces on a gradient from normal to most severely remodeled, we identified a sequence of compositional and molecular changes that associate with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially-resolved characterization of the cellular and molecular programs of PF and control lungs, provide new insights into the heterogeneous pathobiology of PF, and establish analytical approaches which should be broadly applicable to other imaging-based spatial transcriptomic studies.