Leveraging physiology and artificial intelligence to deliver advancements in health care.

Artificial intelligence in health care has experienced remarkable innovation and progress in the last decade. Significant advancements can be attributed to the utilization of artificial intelligence to transform physiology data to advance health care. In this review, we explore how past work has shaped the field and defined future challenges and directions. In particular, we focus on three areas of development. First, we give an overview of artificial intelligence, with special attention to the most relevant artificial intelligence models. We then detail how physiology data have been harnessed by artificial intelligence to advance the main areas of health care: automating existing health care tasks, increasing access to care, and augmenting health care capabilities. Finally, we discuss emerging concerns surrounding the use of individual physiology data and detail an increasingly important consideration for the field, namely the challenges of deploying artificial intelligence models to achieve meaningful clinical impact.

Interrater Agreement of CT Grading of Blunt Splenic Injuries: Does the AAST Grading Need to Be Reimagined?

Introduction: The Revised Organ Injury Scale (OIS) of the American Association for Surgery of Trauma (AAST) is the most widely accepted classification of splenic trauma. The objective of this study was to evaluate inter-rater agreement for CT grading of blunt splenic injuries. Methods: CT scans in adult patients with splenic injuries at a level 1 trauma centre were independently graded by 5 fellowship trained abdominal radiologists using the AAST OIS for splenic injuries - 2018 revision. The inter-rater agreement for AAST CT injury score, as well as low-grade (IIII) versus high-grade (IV-V) splenic injury was assessed. Disagreement in two key clinical scenarios (no injury versus injury, and high versus low grade) were qualitatively reviewed to identify possible sources of disagreement. Results: A total of 610 examinations were included. The inter-rater absolute agreement was low (Fleiss kappa statistic 0.38, P < 0.001), but improved when comparing agreement between low and high grade injuries (Fleiss kappa statistic of 0.77, P < .001). There were 34 cases (5.6%) of minimum two-rater disagreement about no injury vs injury (AAST grade ≥ I). There were 46 cases (7.5%) of minimum two-rater disagreement of low grade (AAST grade I-III) versus high grade (AAST grade IV-V) injuries. Likely sources of disagreement were interpretation of clefts versus lacerations, peri-splenic fluid versus subcapsular hematoma, application of adding multiple low grade injuries to higher grade injuries, and identification of subtle vascular injuries. Conclusion: There is low absolute agreement in grading of splenic injuries using the existing AAST OIS for splenic injuries.

Machine Learning Detection and Characterization of Splenic Injuries on Abdominal Computed Tomography.

BACKGROUND: Multi-detector contrast-enhanced abdominal computed tomography (CT) allows for the accurate detection and classification of traumatic splenic injuries, leading to improved patient management. Their effective use requires rapid study interpretation, which can be a challenge on busy emergency radiology services. A machine learning system has the potential to automate the process, potentially leading to a faster clinical response. This study aimed to create such a system. METHOD: Using the American Association for the Surgery of Trauma (AAST), spleen injuries were classified into 3 classes: normal, low-grade (AAST grade I-III) injuries, and high-grade (AAST grade IV and V) injuries. Employing a 2-stage machine learning strategy, spleens were initially segmented from input CT images and subsequently underwent classification via a 3D dense convolutional neural network (DenseNet). RESULTS: This single-centre retrospective study involved trauma protocol CT scans performed between January 1, 2005, and July 31, 2021, totaling 608 scans with splenic injuries and 608 without. Five board-certified fellowship-trained abdominal radiologists utilizing the AAST injury scoring scale established ground truth labels. The model achieved AUC values of 0.84, 0.69, and 0.90 for normal, low-grade injuries, and high-grade splenic injuries, respectively. CONCLUSIONS: Our findings demonstrate the feasibility of automating spleen injury detection using our method with potential applications in improving patient care through radiologist worklist prioritization and injury stratification. Future endeavours should concentrate on further enhancing and optimizing our approach and testing its use in a real-world clinical environment.

"Transcanal view" computed tomography reformat: Applications for transcanal endoscopic ear surgery.

PURPOSE: Transcanal endoscopic ear surgery (TEES) is an increasingly used surgical approach for otologic surgeries, but no en face preoperative imaging format currently exists. We aim to assess the utility of a transcanal high resolution computed tomography (HRCT) reformat suitable for TEES preoperative planning. MATERIALS AND METHODS: Preoperative HRCTs of patients with middle ear pathologies (cholesteatoma, otosclerosis, and glomus tympanicum) who underwent TEES were obtained. Axial image series were rotated and reformatted -90 or +90 degrees for left and right ear surgeries, respectively, where additional rotation along the left-right axis was performed to align the transcanal series with the plane of the external auditory canal. Quantitative measurements of middle ear structures were recorded. Consecutive transcanal reformatted sections were then reviewed to identify critical middle ear anatomy and pathology with corresponding TEES cases. RESULTS: The aforementioned methodology was used to create three transcanal view HRCTs. The mean left-right axis degree of rotation was 4.0 ± 2.2 degrees. In the cholesteatoma transcanal HRCT, areas of cholesteatoma involvement in middle ear compartments (e.g. epitympanum) and eroded ossicles were successfully identified in the corresponding case. In the otosclerosis transcanal HRCT, areas for potential otosclerotic involvement were visualized such as the round window as well as a low-hanging facial nerve. In the glomus tympanicum transcanal HRCT, the span of the glomus tympanicum was successfully visualized in addition to a high riding jugular bulb. CONCLUSION: A transcanal HRCT reformat may aid preoperative planning for middle ear pathologies. This novel reformat may help highlight patient-specific anatomy.

Efficacy and tolerability of AFPep, a cyclic peptide with anti-breast cancer properties.

PURPOSE: The purpose of this study is to assess the efficacy and safety profile of AFPep, a 9-amino acid cyclic peptide prior to its entry into pre-clinical toxicology analyses en route to clinical trials. METHODS: AFPep was assessed for anti-estrogenic activity in a mouse uterine growth assay and for breast cancer therapeutic efficacy in a human tumor xenograft model in mice. AFPep was assessed for tolerability in a variety of in vivo models, notably including assessment for effects on rat liver and human hepatocellular carcinoma cell lines and xenografts. RESULTS: AFPep arrests the growth of human MCF-7 breast cancer xenografts, inhibits the estrogen-induced growth of mouse uteri, and does not affect liver growth nor stimulate growth of human hepatocellular carcinoma cell lines when growing in vitro or as xenografts in vivo. AFPep is well tolerated in mice, rats, dogs, and primates. CONCLUSIONS: AFPep is effective for the treatment of ER-positive breast cancer and exhibits a therapeutic index that is substantially wider than that for drugs currently in clinical use. The data emphasize the importance of pursuing pre-clinical toxicology studies with the intent to enter clinical trials.

Radiotherapy for the treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma is an aggressive disease that continues to be associated with poor outcomes. Although, traditionally this disease is considered to be resistant to radiotherapy, more recent evidence suggests that radiotherapy can produce positive outcomes. Over the past 15 years, the development of new, highly conformal radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), has enabled investigators to optimise the delivery of high-dose radiotherapy to the whole of the hemithorax. Prospective single-arm trials have shown that the median survival of patients who have completed high-dose hemithoracic radiotherapy after extrapleural pneumonectomy could reach 23·9-39·4 months independent of the chemotherapeutic response, suggesting that IMRT could potentially have an intrinsic benefit to this subset of patients. These observations have led to a change in practice, with the introduction of adjuvant pleural IMRT after pleurectomy-decortication and the development of induction-accelerated hemithoracic IMRT followed by extrapleural pneumonectomy. This Review focuses on recent observations on the role of radiotherapy in the treatment of malignant pleural mesothelioma, with particular emphasis on the results of clinical trials that evaluate the role of high-dose hemithoracic radiotherapy.

Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma.

We studied the impact of natural killer T (NKT) cell activation by alpha-galactocysylceramide (α-GalCer, α-GC) on cancer cell repopulation during chemotherapy in murine mesothelioma. The number of NKT cells was found to be increased during the development of murine mesothelioma. NKT cells specifically recognize α-GC through CD1d resulting in their activation and expansion. Tumor-bearing mice were treated with chemotherapy once weekly, and α-GC was followed after each cycle of chemotherapy. Anti-tumor effect was evaluated on wild-type (WT) and CD1d knockout (CD1dKO) mice. Cancer cell proliferation and apoptosis were evaluated by Ki67 and TUNEL immunohistochemistry. CD4(+) and CD8(+) T cell proportion and activation in tumor, spleen, draining lymph node and peripheral blood were determined by flow cytometry, and gene expression of activated T cell-related cytokines was quantified by reverse transcription PCR. NKT cells were identified by CD1d-α-GC-tetramer staining. In WT mice, tumor growth delay was achieved by cisplatin (Cis), and this effect was improved in combination with α-GC, but α-GC alone had little effect. Cancer cell proliferation during chemotherapy was significantly inhibited by α-GC, while cancer cell death was significantly upregulated. α-GC following chemotherapy resulted in NKT cell expansion and an increase of interferon-γ production in the draining lymph node, blood and spleen. Gene expression of immune-associated cytokines was upregulated. Strikingly, the percentage of inducible T cell co-stimulator(+)CD4 T cells, Th17/Tc17 cells increased in splenocytes. In CD1d KO mice, however, Cis alone was less effective and Cis + α-GC provided no additional benefit over Cis alone. α-GC alone had minimal effect in both mice. NKT activation between cycles of chemotherapy could improve the outcome of mesothelioma treatment.

Radiology advocacy: Promoting collaboration between trainees and professional societies.

From mammographic screening guidelines to resident work hour regulations, public policy affects every aspect of the practice of radiology and ultimately determines how radiological care is delivered to patients. Shaping public policy through advocacy is therefore critical to ensure patient access to equitable, high-quality radiological care. In advocacy, individual practicing radiologists and radiology trainees can increase the scope of their influence by collaborating with professional radiology societies. When radiology trainees participate in organized radiology advocacy, they learn about regulatory and legislative issues that will affect their careers, and they learn how to effect policy change. Radiology societies in turn benefit from trainee involvement, as engaging trainees early in their careers leads to more robust future participation and leadership. To encourage trainee involvement, radiology societies can engage individual residency programs and medical student radiology interest groups, invest in trainee-focused events, and maximize the number of positions of responsibility open to trainees. To circumvent the barriers to participation that many trainees face, radiology societies can make meeting proceedings free and available through virtual mediums. Through active collaboration, trainees and professional societies can help assure a bright future for radiologists and patients in need of radiological care.

Optimization of diagnostic and procedural codes to identify patients with acute invasive fungal sinusitis.

KEY POINTS: Acute invasive fungal sinusitis (IFS) is a rare disease with high mortality There is no designated International Classification of Diseases code for IFS We propose a novel method to identify IFS using optimized codes complemented by medications.

Large Animal Translational Validation of 3 Mitral Valve Repair Operations for Mitral Regurgitation Using a Mitral Valve Prolapse Model: A Comprehensive In Vivo Biomechanical Engineering Analysis.

BACKGROUND: Various mitral repair techniques have been described. Though these repair techniques can be highly effective when performed correctly in suitable patients, limited quantitative biomechanical data are available. Validation and thorough biomechanical evaluation of these repair techniques from translational large animal in vivo studies in a standardized, translatable fashion are lacking. We sought to evaluate and validate biomechanical differences among different mitral repair techniques and further optimize repair operations using a large animal mitral valve prolapse model. METHODS: Male Dorset sheep (n=20) had P2 chordae severed to create the mitral valve prolapse model. Fiber Bragg grating force sensors were implanted to measure chordal forces. Ten sheep underwent 3 randomized, paired mitral valve repair operations: neochord repair, nonresectional leaflet remodeling, and triangular resection. The other 10 sheep underwent neochord repair with 2, 4, and 6 neochordae. Data were collected at baseline, mitral valve prolapse, and after each repair. RESULTS: All mitral repair techniques successfully eliminated regurgitation. Compared with mitral valve prolapse (0.54±0.18 N), repair using neochord (0.37±0.20 N; P=0.02) and remodeling techniques (0.30±0.15 N; P=0.001) reduced secondary chordae peak force. Neochord repair further decreased primary chordae peak force (0.21±0.14 N) to baseline levels (0.20±0.17 N; P=0.83), and was associated with lower primary chordae peak force compared with the remodeling (0.34±0.18 N; P=0.02) and triangular resectional techniques (0.36±0.27 N; P=0.03). Specifically, repair using 2 neochordae resulted in higher peak primary chordal forces (0.28±0.21 N) compared with those using 4 (0.22±0.16 N; P=0.02) or 6 neochordae (0.19±0.16 N; P=0.002). No difference in peak primary chordal forces was observed between 4 and 6 neochordae (P=0.05). Peak forces on the neochordae were the lowest using 6 neochordae (0.09±0.11 N) compared with those of 4 neochordae (0.15±0.14 N; P=0.01) and 2 neochordae (0.29±0.18 N; P=0.001). CONCLUSIONS: Significant biomechanical differences were observed underlying different mitral repair techniques in a translational large animal model. Neochord repair was associated with the lowest primary chordae peak force compared to the remodeling and triangular resectional techniques. Additionally, neochord repair using at least 4 neochordae was associated with lower chordal forces on the primary chordae and the neochordae. This study provided key insights about mitral valve repair optimization and may further improve repair durability.

Thrombotic microangiopathy following chimeric antigen receptor T-cell therapy.

INTRODUCTION: Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia and is associated with a variety of conditions and following hematopoietic stem cell transplantation. Chimeric antigen receptor T-cell (CAR-T) therapy is a novel immunotherapeutic approach using genetically modified autologous T cells. CAR-T therapy has been linked with injuries to vascular endothelium, but a direct association between CAR-T and TMA has not been reported. CASE REPORTS: Two cases of TMAs following CAR-T treatment are reported here. In each case, clinical evidence of kidney injury, thrombocytopenia, and hemolytic anemia became apparent 2 - 3 months following CAR-T infusion. We describe the clinical course, management, and outcome of these experiences. DISCUSSION/CONCLUSION: CAR-T cell therapy-associated TMA (CAR-T TMA) appear to be an entity that shares overlapping clinical features with transplant-associated TMA (TA-TMA). Based on our preliminary clinical observations, we discuss the best clinical diagnosis/classification criteria, underlying pathophysiology, and the implication of the apparently self-limiting course. With increasing use of CAR-T cell treatment in hematologic malignancies, systematic studies will be necessary to improve management of CAR-T TMA.

Evaluating the accuracy of speech to text applications for cochlear implant candidates during COVID-19.

OBJECTIVES: Universal mask wearing due to COVID-19 has introduced barriers to clear communication. In hearing impaired individuals this can impact informed surgical consent. For cochlear implant candidates, who do not rely on sign language, real-time transcription with a stenographer (CART) is the gold-standard in assistive technologies. If CART is not available, speech to text (STT) applications have been advertised as solutions, but their transcription accuracy with or without an N95 mask is not well-established. Herein, we sought to investigate the transcription accuracy of three STT solutions for iPhone and compare their performance to the CART service at our institution. METHODS: Three native English speakers and three non-native English speakers read two passages (a cochlear implant consent and the non-medical 'Rainbow passage') with and without an N95 mask. Error rates from the comparison of the transcript (from either the STT app or CART) with the original passage were calculated. RESULTS: The CART service had the lowest error rate of all testing conditions (4.79-7.14%). Ava 24/7 (15.0 ± 9.49%) and the iPhone dictation (15.6 ± 6.65%) had significantly lower average error rates than the Live Transcribe (37.7 ± 20.3%) (P < 0.0001) application. Neither the presence of an N95 nor the type of passage had a statistically significant impact on the error rate. CONCLUSION: CART should be used to augment communication with patients who are hard of hearing. If CART is not available, a STT application such as Ava 24/7 or the native iPhone dictation application may be considered, even in the context of medical terminology.

Tachycardia-induced metabolic rewiring as a driver of contractile dysfunction.

Prolonged tachycardia-a risk factor for cardiovascular morbidity and mortality-can induce cardiomyopathy in the absence of structural disease in the heart. Here, by leveraging human patient data, a canine model of tachycardia and engineered heart tissue generated from human induced pluripotent stem cells, we show that metabolic rewiring during tachycardia drives contractile dysfunction by promoting tissue hypoxia, elevated glucose utilization and the suppression of oxidative phosphorylation. Mechanistically, a metabolic shift towards anaerobic glycolysis disrupts the redox balance of nicotinamide adenine dinucleotide (NAD), resulting in increased global protein acetylation (and in particular the acetylation of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase), a molecular signature of heart failure. Restoration of NAD redox by NAD+ supplementation reduced sarcoplasmic/endoplasmic reticulum Ca2+-ATPase acetylation and accelerated the functional recovery of the engineered heart tissue after tachycardia. Understanding how metabolic rewiring drives tachycardia-induced cardiomyopathy opens up opportunities for therapeutic intervention.

Educational Quality of YouTube Cholesteatoma Surgery Videos: Areas for Improvement.

Otolaryngology surgical education continues to evolve where trainees increasingly use videos to learn technical skills. Trainees commonly use YouTube, but no study to date has evaluated the educational quality (EQ) of otologic surgical videos on YouTube. We aim to assess the EQ of cholesteatoma surgical videos. Cholesteatoma surgical videos were queried using YouTube search terms, assessed using LAParoscopic surgery Video Educational GuidelineS (LAP-VEGaS), a validated assessment tool for publication, and categorized into low (0-6), medium (7-12), and high (13-18) EQ groups. In total, 74 videos were identified (mean LAP-VEGaS score = 9.6 ± 4.0) and 44.6% had medium EQ. Videos commonly lacked graphic aids to highlight anatomy (71.6%) and postprocedural outcomes (68.9%). LAP-VEGaS scores were greater in videos originating from US surgeons compared to non-US surgeons (12.4 ± 3.4 vs 8.0 ± 3.5; P < .001). Our study highlights that otolaryngology trainees may experience difficulty finding high-EQ cholesteatoma surgery videos on YouTube. Areas for improved EQ content are discussed. Level of evidence: IV.

Generation of two induced pluripotent stem cell lines from dilated cardiomyopathy patients caused by heterozygous mutations in the HCN4 gene.

Dilated cardiomyopathy (DCM) is a progressive heart muscle disease that can culminate with heart failure and death. Mutations in several genes can cause DCM, including hyperpolarization-activated cyclic nucleotide-gated channel (HCN4), which has a critical function in the autonomic control of the heart rate. Here, we generated two human induced pluripotent stem cell (iPSC) lines generated from two DCM patients carrying variants in the HCN4 gene (c.2587G > T and c.2846G > A). Both lines display normal karyotype, typical morphology of pluripotent stem cells, and differentiate into all three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of DCM.

Information scarcity among otolaryngology applicants: A review of the largest database of programs.

Objective: Otolaryngology residency applicants face challenges finding accurate information about training programs. Social media platforms are not verified, and official training program websites are not standardized. Currently, the American Medical Association's Fellowship and Residency Electronic Interactive Database (FREIDA) is the most comprehensive sanctioned and verified otolaryngology residency program database. However, the exact amount of information shared by individual programs included is not presently known. Methods: Herein, we analyzed the available data on all 124 otolaryngology residency programs in FREIDA to assess the completeness of the database. Results: While every program listed an address, contact email, and the name of the program director, more than half of programs (n = 65, 52.4%) did not provide additional information. Most programs (70.2%) did not include a one-paragraph program description. Conclusion: Our findings suggest that while FREIDA is the only sanctioned online database for residency programs, it is inadequately populated with detailed program information. Level of Evidence: N/A.

Intracochlear New Fibro-Ossification and Neuronal Degeneration Following Cochlear Implant Electrode Translocation: Long-Term Histopathological Findings in Humans.

OBJECTIVE: We aim to assess the histopathology of human temporal bones (TBs) with evidence of cochlear implantation (CI) electrode scalar translocation. STUDY DESIGN: Otopathology study. SETTING: Otopathology laboratory. PATIENTS: TBs from patients who had a history of CI and histopathological evidence of interscalar translocation. Specimens with electrode placed entirely within the ST served as controls. INTERVENTION: Histopathological assessment of human TBs. MAIN OUTCOME MEASURES: TBs from each patient were harvested postmortem and histologically analyzed for intracochlear changes in the context of CI electrode translocation and compared to controls. Intracochlear new fibro-ossification, and spiral ganglion neuron (SGN) counts were assessed. Postoperative word recognition scores (WRS) were also compared. RESULTS: Nineteen human TBs with electrode translocation and eight controls were identified. The most common site of translocation was the ascending limb of the basal turn (n = 14 TBs). The average angle of insertion at the point of translocation was 159°â€Š±â€Š79°. Eighteen translocated cases presented moderate fibroosseous changes in the basal region of the cochlea, extending to the translocation point and/or throughout the electrode track in 42%. Lower SGN counts were more pronounced in translocated cases compared to controls, with a significant difference for segment II (p = 0.019). Although final postoperative hearing outcomes were similar between groups, translocated cases had slower rate of improvement in WRS (p = 0.021). CONCLUSIONS: Cochlear implant electrode translocation was associated with greater fibroosseous formation and lower SGN population. Our findings suggest that scalar translocations may slow the rate of improvement in WRS overtime as compared to atraumatic electrode insertions.Level of evidence: IV.

A Subset of Intracanalicular Vestibular Schwannomas Demonstrates Minimal Growth Over a 10-Year Period.

OBJECTIVE: Vestibular schwannomas (VS) commonly undergo magnetic resonance imaging (MRI) surveillance, but long-term data to support the ideal frequency is limited. Herein, we aim to investigate intracanalicular VS growth predictors and long-term growth rates (GR). STUDY DESIGN: Retrospective chart review. SETTING: Two tertiary care centers. PATIENTS: Sporadic intracanalicular VS with initial conservative management and at least two sequential MRIs. INTERVENTION: Serial MRI. MAIN OUTCOME MEASURES: VS were categorized by baseline internal auditory canal tertile sublocalization (fundus, midpoint, porus) and size (≤100, 100-200, >200 mm3). Throughout follow-up, volumetric GR (mm3/yr) were determined (baseline-3 yrs, 3-5 yrs, 5-10 yrs) and treatment rates were assessed. RESULTS: Ninety-nine intracanalicular VS were identified (mean follow-up of 6.1 ±â€Š4.5 yrs). Mean GR before 5-year follow-up were comparable for baseline tertile involvement and size. After 5-year follow-up, mean GR of VS involving the fundus at baseline were lower than those involving the midpoint and fundus (6.17 ±â€Š21.16 and 119.74 ±â€Š117.57 mm3/yr, respectively; p = 0.034). Mean GR of VS with less than or equal to 100 mm3 at baseline (-7.29 ±â€Š25.44 mm3/yr) were lower than those with 100 to 200 mm3 (86.55 ±â€Š103.99 mm3/yr; p = 0.011) and more than 200 mm3 (45.70 ±â€Š35.71 mm3/yr; p = 0.031). Vestibular schwannomas involving the midpoint and fundus had greater treatment rates compared with VS involving only the fundus (p < 0.001). CONCLUSIONS: Baseline tertile involvement and size may predict long-term intracanalicular VS growth where fundal tumors or those less than or equal to 100 mm3 exhibit little long-term growth. Extending surveillance after 5-year follow-up may be reasonable for fundal VS.

A neonatal leporine model of age-dependent natural heart regeneration after myocardial infarction.

OBJECTIVES: Neonatal rodents and piglets naturally regenerate the injured heart after myocardial infarction. We hypothesized that neonatal rabbits also exhibit natural heart regeneration after myocardial infarction. METHODS: New Zealand white rabbit kits underwent sham surgery or left coronary ligation on postnatal day 1 (n = 94), postnatal day 4 (n = 11), or postnatal day 7 (n = 52). Hearts were explanted 1 day postsurgery to confirm ischemic injury, at 1 week postsurgery to assess cardiomyocyte proliferation, and at 3 weeks postsurgery to assess left ventricular ejection fraction and scar size. Data are presented as mean ± standard deviation. RESULTS: Size of ischemic injury as a percentage of left ventricular area was similar after myocardial infarction on postnatal day 1 versus on postnatal day 7 (42.3% ± 5.4% vs 42.3% ± 4.7%, P = .9984). Echocardiography confirmed severely reduced ejection fraction at 1 day after postnatal day 1 myocardial infarction (33.7% ± 5.3% vs 65.2% ± 5.5% for postnatal day 1 sham, P = .0001), but no difference at 3 weeks after postnatal day 1 myocardial infarction (56.0% ± 4.0% vs 58.0% ± 3.3% for postnatal day 1 sham, P = .2198). Ejection fraction failed to recover after postnatal day 4 myocardial infarction (49.2% ± 1.8% vs 58.5% ± 5.8% for postnatal day 4 sham, P = .0109) and postnatal day 7 myocardial infarction (39.0% ± 7.8% vs 60.2% ± 5.0% for postnatal day 7 sham, P &lt; .0001). At 3 weeks after infarction, fibrotic scar represented 5.3% ± 1.9%, 14.3% ± 4.9%, and 25.4% ± 13.3% of the left ventricle area in the postnatal day 1, postnatal day 4, and postnatal day 7 groups, respectively. An increased proportion of peri-infarct cardiomyocytes expressed Ki67 (15.9% ± 1.8% vs 10.2% ± 0.8%, P = .0039) and aurora B kinase (4.0% ± 0.9% vs 1.5% ± 0.6%, P = .0088) after postnatal day 1 myocardial infarction compared with sham, but no increase was observed after postnatal day 7 myocardial infarction. CONCLUSIONS: A neonatal leporine myocardial infarction model reveals that newborn rabbits are capable of age-dependent natural heart regeneration.

Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

Retinoic acid receptor responder 1 (RARRES1) is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines in vitro. Here, we created constitutive Rarres1 knockout (Rarres1-/-) mouse models to study RARRES1 function in vivo. Rarres1-/- embryonic fibroblasts regulated tubulin glutamylation, cell metabolism, and survival, recapitulating RARRES1 function in immortalized cell lines. In two mouse strains, loss of Rarres1 led to a markedly increased dose-dependent incidence of follicular lymphoma (FL). Prior to lymphoma formation, Rarres1-/- B cells have compromised activation, maturation, differentiation into antibody-secreting plasma cells, and cell cycle progression. Rarres1 ablation increased B cell survival and led to activation of the unfolded protein response (UPR) and heat shock response (HSR). Rarres1 deficiency had differential effects on cellular metabolism, with increased bioenergetic capacity in fibroblasts, and minor effects on bioenergetics and metabolism in B cells. These findings reveal that RARRES1 is a bona fide tumor suppressor in vivo and the deletion in mice promotes cell survival, and reduces B cell differentiation with B cell autonomous and non-autonomous functions.