En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.

Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, "in-a-dish" genotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.

In older patients with AF and frailty, switching from VKA to NOAC therapy increased a composite of major or CRNM bleeding at 12 mo.

SOURCE CITATION: Joosten LP, van Doorn S, van de Ven PM, et al. Safety of switching from a vitamin K antagonist to a non-vitamin K antagonist oral anticoagulant in frail older patients with atrial fibrillation: results of the FRAIL-AF randomized controlled trial. Circulation. 2024;149:279-289. 37634130.

In AF, underdosing of DOACs was not linked to reduced bleeding.

SOURCE CITATION: Caso V, de Groot JR, Sanmartin Fernandez M, et al. Outcomes and drivers of inappropriate dosing of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a systematic review and meta-analysis. Heart. 2023;109:178-85. 36316100.

Outpatient Treatment of Confirmed COVID-19: Living, Rapid Practice Points From the American College of Physicians (Version 2).

DESCRIPTION: Evidence for the use of outpatient treatments in adults with confirmed COVID-19 continues to evolve with new data. This is version 2 of the American College of Physicians (ACP) living, rapid practice points focusing on 22 outpatient treatments for COVID-19, specifically addressing the dominant SARS-CoV-2 Omicron variant. METHODS: The Population Health and Medical Science Committee (formerly the Scientific Medical Policy Committee) developed this version of the living, rapid practice points on the basis of a living, rapid review done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems). This topic will be maintained as living and rapid by continually monitoring and assessing the impact of new evidence. PRACTICE POINT 1: Consider molnupiravir to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. PRACTICE POINT 2: Consider nirmatrelvir-ritonavir combination therapy to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. PRACTICE POINT 3: Do not use ivermectin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 4: Do not use sotrovimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.

Cortical perfusion measurements with laser speckle contrast imaging during adenosine induced cardiac arrest for aneurysm clipping: a case report.

Adenosine induced cardiac arrest (AiCA) is one of the methods used to facilitate microsurgical aneurysm clipping by providing more visibility and less pressure in the aneurysmal sac and neighboring vessels. We report the use of laser speckle contrast imaging (LSCI) during AiCA to monitor the changes in pulsation and perfusion on the cortical surface during adenosine induced cardiac arrest for aneurysm clipping surgery. Application of this technology for perfusion monitoring may improve workflow and surgical guidance and provide valuable feedback continuously throughout the procedure. ClinicalTrials.gov identifier: NCT0502840.

Fixed-Dose Phenobarbital Versus As-Needed Benzodiazepines for the Management of Alcohol Withdrawal in Acute Care General Internal Medicine.

OBJECTIVES: The management of patients at risk of severe alcohol withdrawal is challenging because conventional treatment with as-needed benzodiazepines may be ineffective. We created a fixed-dose phenobarbital protocol and compared patient outcomes using this protocol with an as-needed benzodiazepine protocol. METHODS: Patients admitted from the emergency department (ED) to General Medicine from January 1 to June 30, 2022 and treated for alcohol withdrawal with a novel phenobarbital protocol were compared with all of the patients admitted from the ED to General Medicine from January 1 to June 30, 2018, and treated with as-needed benzodiazepines. The primary outcome was a composite of intensive care unit (ICU) transfer or mortality. Secondary outcomes included mortality, ICU transfer, seizure, length of stay, excess sedation, delirium, against medical advice discharge, 30-day re-admission, 30-day ED reevaluation, and antipsychotic use. RESULTS: There were 54 patients in the phenobarbital group and 197 in the benzodiazepine group. The phenobarbital group was less medically complex but had more risk factors for severe withdrawal. There was no difference in the primary outcome, although there was a trend toward benefit in the phenobarbital group (3.7 vs 8.1%, P = 0.26), and there was a lower incidence of delirium in the phenobarbital cohort (0 vs 8.6%, P = 0.03). Secondary outcome trends favored phenobarbital, with lower mortality, ICU transfer, seizure, oversedation, against medical advice discharge, and 30-day re-admissions. A subgroup analysis accounting for differences in patient populations in the primary analysis found similar results. CONCLUSIONS: Phenobarbital is as safe and effective as benzodiazepine-based protocols for the treatment of high-risk alcohol withdrawal, with lower rates of delirium.

Student High Value Care Initiative: a Longitudinal Model for Student-Led Implementation and Scholarship.

BACKGROUND: Educating medical trainees to practice high value care is a critical component to improving quality of care and should be introduced at the beginning of medical education. AIM: To create a successful educational model that provides medical students and junior faculty with experiential learning in quality improvement and mentorship opportunities, and produce effective quality initiatives. SETTING: A tertiary medical center affiliated with a medical school in New York City. PARTICIPANTS: First year medical students, junior faculty in hospital medicine, and a senior faculty course director. PROGRAM DESCRIPTION: The Student High Value Care initiative is a longitudinal initiative comprised of six core elements: (1) project development, (2) value improvement curriculum, (3) mentorship, (4), Institutional support, (5) scholarship, and (6) student leadership. PROGRAM EVALUATION: During the first 3 years, 68 medical students and ten junior faculty participated in 10 quality improvement projects. Nine projects were successful in their measured outcomes, with statistically significant improvements. Nine had an abstract accepted to a regional or national meeting, and seven produced publications in peer-reviewed literature. DISCUSSION: In the first 3 years of the initiative, we successfully engaged medical students and junior faculty to create and support the implementation of successful quality improvement initiatives. Since that time, the program continues to offer meaningful mentorship and scholarship opportunities.

Eccrine Porocarcinoma of the Vulva With Sarcomatoid Transformation, a New Human Papillomavirus-associated Malignancy? Case Report and Review of the Literature.

Eccrine porocarcinoma is a rare cutaneous neoplasm, and rarer still in the anogenital region. In the vulva, the most common carcinoma by far is squamous cell carcinoma; however, eccrine porocarcinoma can arise at this site. As the distinction between porocarcinoma and squamous cell carcinoma has important prognostic implications at other cutaneous sites, it stands to reason that it may have these same implications in the vulva. We present a case of an eccrine porocarcinoma in the vulva of a 70-year-old woman that, in addition, showed sarcomatoid transformation. This tumor harbored human papillomavirus-18 DNA and mRNA, raising the question of the role of the oncogenic virus in sweat gland neoplasms of the vulva.

Analysing Monday discharges to identify lost opportunities for weekend discharge.

Lower rates of hospital discharge occur on weekends compared with weekdays. The authors performed a retrospective chart review of Monday discharges from the Hospital Medicine service at an academic hospital over a 3-month period to identify reasons for delayed discharge despite medical stability. Of 202 eligible patients, 81 (40%) had documentation indicating stability for earlier discharge. Common causes included bed availability or insurance authorisation at a skilled nursing facility, home care services and patient/family disagreement with discharge.

What Is the Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Infection? Rapid, Living Practice Points From the American College of Physicians (Version 2).

DESCRIPTION: The Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) developed these living, rapid practice points to summarize the current best available evidence on the antibody response to SARS-CoV-2 infection and protection against reinfection with SARS-CoV-2. This is version 2 of the ACP practice points, which serves to update version 1, published on 16 March 2021. These practice points do not evaluate vaccine-acquired immunity or cellular immunity. METHODS: The SMPC developed this version of the living, rapid practice points based on an updated living, rapid, systematic review conducted by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality. PRACTICE POINT 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection. PRACTICE POINT 2: Do not use SARS-CoV-2 antibody tests to predict the degree or duration of natural immunity conferred by antibodies against reinfection, including natural immunity against different variants. RETIREMENT FROM LIVING STATUS: Although natural immunity remains a topic of scientific interest, this topic is being retired from living status given the availability of effective vaccines for SARS-CoV-2 and widespread recommendations for and prevalence of their use. Currently, vaccination is the best clinical recommendation for preventing infection, reinfection, and serious illness from SARS-CoV-2 and its variants.

Nanoparticle Delivery of STAT3 Alleviates Pulmonary Hypertension in a Mouse Model of Alveolar Capillary Dysplasia.

BACKGROUND: Pulmonary hypertension (PH) is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. Although the loss of alveolar microvasculature causes PH in patients with ACDMPV, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. METHODS: We used echocardiography, RV catheterization, immunostaining, and biochemical methods to examine lung and heart remodeling and RV output in Foxf1WT/S52F mice carrying the S52F Foxf1 mutation (identified in patients with ACDMPV). The ability of Foxf1WT/S52F mutant embryonic stem cells to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a nonintegrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1WT/S52F mice and determine its effects on PH and RV hypertrophy. RESULTS: Foxf1WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization, and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse embryonic stem cells carrying the S52F Foxf1 mutation were used to produce chimeras through blastocyst complementation and to demonstrate that Foxf1WT/S52F embryonic stem cells have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1WT/S52F mice from RV hypertrophy and PH, improved survival, and decreased fibrotic lung remodeling. CONCLUSIONS: Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.

High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell-Derived Organoids.

BACKGROUND & AIMS: Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)-based screening model for analyzing DILI pathology at organoid resolution. METHODS: We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform. RESULTS: HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9-based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis. CONCLUSIONS: Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.

Segmentation-Less, Automated, Vascular Vectorization.

Recent advances in two-photon fluorescence microscopy (2PM) have allowed large scale imaging and analysis of blood vessel networks in living mice. However, extracting network graphs and vector representations for the dense capillary bed remains a bottleneck in many applications. Vascular vectorization is algorithmically difficult because blood vessels have many shapes and sizes, the samples are often unevenly illuminated, and large image volumes are required to achieve good statistical power. State-of-the-art, three-dimensional, vascular vectorization approaches often require a segmented (binary) image, relying on manual or supervised-machine annotation. Therefore, voxel-by-voxel image segmentation is biased by the human annotator or trainer. Furthermore, segmented images oftentimes require remedial morphological filtering before skeletonization or vectorization. To address these limitations, we present a vectorization method to extract vascular objects directly from unsegmented images without the need for machine learning or training. The Segmentation-Less, Automated, Vascular Vectorization (SLAVV) source code in MATLAB is openly available on GitHub. This novel method uses simple models of vascular anatomy, efficient linear filtering, and vector extraction algorithms to remove the image segmentation requirement, replacing it with manual or automated vector classification. Semi-automated SLAVV is demonstrated on three in vivo 2PM image volumes of microvascular networks (capillaries, arterioles and venules) in the mouse cortex. Vectorization performance is proven robust to the choice of plasma- or endothelial-labeled contrast, and processing costs are shown to scale with input image volume. Fully-automated SLAVV performance is evaluated on simulated 2PM images of varying quality all based on the large (1.4×0.9×0.6 mm3 and 1.6×108 voxel) input image. Vascular statistics of interest (e.g. volume fraction, surface area density) calculated from automatically vectorized images show greater robustness to image quality than those calculated from intensity-thresholded images.

Post-TKA abelacimab reduced VTE at 8 to 12 d compared with enoxaparin.

SOURCE CITATION: Verhamme P, Yi BA, Segers A, et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med. 2021;385:609-17. 34297496.

A Window of Vascular Plasticity Coupled to Behavioral Recovery after Stroke.

Stroke causes remodeling of vasculature surrounding the infarct, but whether and how vascular remodeling contributes to recovery are unclear. We established an approach to monitor and compare changes in vascular structure and blood flow with high spatiotemporal precision after photothrombotic infarcts in motor cortex using longitudinal 2-photon and multiexposure speckle imaging in mice of both sexes. A spatially graded pattern of vascular structural remodeling in peri-infarct cortex unfolded over the first 2 weeks after stroke, characterized by vessel loss and formation, and selective stabilization of a subset of new vessels. This vascular structural plasticity was coincident with transient activation of transcriptional programs relevant for vascular remodeling, reestablishment of peri-infarct blood flow, and large improvements in motor performance. Local vascular plasticity was strongly predictive of restoration of blood flow, which was in turn predictive of behavioral recovery. These findings reveal the spatiotemporal evolution of vascular remodeling after stroke and demonstrate that a window of heightened vascular plasticity is coupled to the reestablishment of blood flow and behavioral recovery. Our findings support that neovascularization contributes to behavioral recovery after stroke by restoring blood flow to peri-infarct regions. These findings may inform strategies for enhancing recovery from stroke and other types of brain injury.SIGNIFICANCE STATEMENT An improved understanding of neural repair could inform strategies for enhancing recovery from stroke and other types of brain injury. Stroke causes remodeling of vasculature surrounding the lesion, but whether and how the process of vascular remodeling contributes to recovery of behavioral function have been unclear. Here we used longitudinal in vivo imaging to track vascular structure and blood flow in residual peri-infarct cortex after ischemic stroke in mice. We found that stroke created a restricted period of heightened vascular plasticity that was associated with restoration of blood flow, which was in turn predictive of recovery of motor function. Therefore, our findings support that vascular remodeling facilitates behavioral recovery after stroke by restoring blood flow to peri-infarct cortex.

Mathematical synthesis of the cortical circulation for the whole mouse brain-part II: Microcirculatory closure.

Recent advancements in multiphoton imaging and vascular reconstruction algorithms have increased the amount of data on cerebrovascular circulation for statistical analysis and hemodynamic simulations. Experimental observations offer fundamental insights into capillary network topology but mainly within a narrow field of view typically spanning a small fraction of the cortical surface (less than 2%). In contrast, larger-resolution imaging modalities, such as computed tomography (CT) or magnetic resonance imaging (MRI), have whole-brain coverage but capture only larger blood vessels, overlooking the microscopic capillary bed. To integrate data acquired at multiple length scales with different neuroimaging modalities and to reconcile brain-wide macroscale information with microscale multiphoton data, we developed a method for synthesizing hemodynamically equivalent vascular networks for the entire cerebral circulation. This computational approach is intended to aid in the quantification of patterns of cerebral blood flow and metabolism for the entire brain. In part I, we described the mathematical framework for image-guided generation of synthetic vascular networks covering the large cerebral arteries from the circle of Willis through the pial surface network leading back to the venous sinuses. Here in part II, we introduce novel procedures for creating microcirculatory closure that mimics a realistic capillary bed. We demonstrate our capability to synthesize synthetic vascular networks whose morphometrics match empirical network graphs from three independent state-of-the-art imaging laboratories using different image acquisition and reconstruction protocols. We also successfully synthesized twelve vascular networks of a complete mouse brain hemisphere suitable for performing whole-brain blood flow simulations. Synthetic arterial and venous networks with microvascular closure allow whole-brain hemodynamic predictions. Simulations across all length scales will potentially illuminate organ-wide supply and metabolic functions that are inaccessible to models reconstructed from image data with limited spatial coverage.

Risk Factors for Mortality in Patients with COVID-19 in New York City.

BACKGROUND: New York City emerged as an epicenter of the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVE: To describe the clinical characteristics and risk factors associated with mortality in a large patient population in the USA. DESIGN: Retrospective cohort study. PARTICIPANTS: 6493 patients who had laboratory-confirmed COVID-19 with clinical outcomes between March 13 and April 17, 2020, who were seen in one of the 8 hospitals and/or over 400 ambulatory practices in the New York City metropolitan area MAIN MEASURES: Clinical characteristics and risk factors associated with in-hospital mortality. KEY RESULTS: A total of 858 of 6493 (13.2%) patients in our total cohort died: 52/2785 (1.9%) ambulatory patients and 806/3708 (21.7%) hospitalized patients. Cox proportional hazard regression modeling showed an increased risk of in-hospital mortality associated with age older than 50 years (hazard ratio [HR] 2.34, CI 1.47-3.71), systolic blood pressure less than 90 mmHg (HR 1.38, CI 1.06-1.80), a respiratory rate greater than 24 per min (HR 1.43, CI 1.13-1.83), peripheral oxygen saturation less than 92% (HR 2.12, CI 1.56-2.88), estimated glomerular filtration rate less than 60 mL/min/1.73m2 (HR 1.80, CI 1.60-2.02), IL-6 greater than 100 pg/mL (HR 1.50, CI 1.12-2.03), D-dimer greater than 2 mcg/mL (HR 1.19, CI 1.02-1.39), and troponin greater than 0.03 ng/mL (HR 1.40, CI 1.23-1.62). Decreased risk of in-hospital mortality was associated with female sex (HR 0.84, CI 0.77-0.90), African American race (HR 0.78 CI 0.65-0.95), and hydroxychloroquine use (HR 0.53, CI 0.41-0.67). CONCLUSIONS: Among patients with COVID-19, older age, male sex, hypotension, tachypnea, hypoxia, impaired renal function, elevated D-dimer, and elevated troponin were associated with increased in-hospital mortality and hydroxychloroquine use was associated with decreased in-hospital mortality.

Histopathology after lidocaine/prilocaine cream administration for vulvar biopsy.

BACKGROUND: Case series have described disruptive histopathologic changes following lidocaine/prilocaine cream anesthetic for biopsies. METHODS: A study of histopathologic changes was performed following a randomized trial comparing topical lidocaine/prilocaine cream to 1% lidocaine injection anesthesia for vulvar biopsy. Histopathology was reviewed by two independent dermatopathologists blinded to the type of anesthetic. Specimens were scored on six histopathologic criteria described in the literature. Individual scores for each histopathologic feature and the total score across features were compared between the two groups using marginal models with generalized estimating equations. RESULTS: Of 37 specimens reviewed, 19 were randomized to lidocaine/prilocaine cream and 18 to 1% lidocaine. Subjects exposed to lidocaine/prilocaine had the following odds of histopathologic changes, relative to lidocaine-exposed subjects: acantholysis (odds ratio 2.48; 95% confidence intervals [CI] 0.51, 12.06), clefting (2.42; 0.64, 9.14), pallor/necrosis (1.13; 0.28, 4.50), spongiosis (0.71; 0.18, 2.85), and papillary dermal edema (1.17; 0.41, 3.29). Total scores were not significantly different between treatment arms (risk ratio 0.98; 0.71, 1.35). CONCLUSION: This histopathologic analysis of a randomized trial between lidocaine/prilocaine cream and injected lidocaine as anesthesia for vulvar biopsy shows the absence of significant disruptive histopathologic features secondary to the type of anesthetic. Additional studies in different clinical contexts are warranted.

The scale of Nigeria's involvement in the trans-national illegal pangolin trade: Temporal and spatial patterns and the effectiveness of wildlife trade regulations.

The Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) prohibits commercial trans-national trade in pangolin specimens. However, African pangolins are continually trafficked to Asia for traditional medicine, with Nigeria considered a key hub. Using reported Nigeria-linked pangolin seizure data and interviews with Nigerian law enforcement officials, we a) characterised Nigeria's involvement in global pangolin trafficking January 2010-September 2021, particularly observing trafficking trends after pangolin's CITES Appendix I listing; b) estimated the minimum number of pangolins whose scales are in Nigeria-linked seizures January 2010-September 2021, and; c) assessed ongoing efforts within Nigeria to curb pangolin trafficking. Nigeria-linked seizures involved 190,407 kg of pangolin derivatives (99.9% scales) from a minimum of 799,343 pangolins (95% confidence interval; 625,944-996,353) of four species (see caveats in Methods). All shipments confiscated in transit were destined for Asia, with a rapid increase in the mass of maritime shipments over time. Furthermore, stockpiling of pangolin derivatives for overseas shipment is perhaps a prominent trafficking model in Nigeria. Nigeria's law enforcement efforts improved from 2017, the same year Nigeria apparently began playing a hub role. The impact of pangolin's CITES Appendix I listing on pangolin trafficking was unclear, as the marked rise in seizures from 2017 when the listing became effective, coincided with improvements in Nigerian law enforcement efforts. COVID-19-induced travel restrictions likely reduced trafficking activities in 2020 but activities may have fully resumed in 2021. This study provides new information to inform effective enforcement and policy formulation efforts to protect African pangolins.

Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia.

Rationale: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD.Objectives: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or FOXF1 (forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.Methods: Newborn mice were exposed to 75% O2 for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with Foxm1 or Foxf1 cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator.Measurements and Main Results: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood.Conclusions: Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.