Transcatheter aortic valve replacement planning with cardiac computed tomography in quadricuspid aortic valve stenosis: a case series.

Background: The presence of severe aortic stenosis in quadricuspid aortic valve (QAV) is an extremely rare combination, and it is unknown whether transcatheter aortic valve replacement (TAVR) is a safe option due to the low incidence. Case summary: We present two patients diagnosed with severe aortic stenosis with QAV morphology type 1 (Nakamura classification). All patients presented to our hospital for evaluation because of worsening functional class, dyspnoea, or syncope. During tomographic planning, the aortic annulus was measured at the level of the deepest sinus for the selection of the number of devices. Due to the presence of four cusps, the smallest cusp was excluded, and three sinuses were virtualized for placement of the pigtail catheter during the procedure. Without complications, a 23 mm Edwards SAPIEN 3 was deployed through the femoral artery in both patients. Control aortography showed no valve leakage or regurgitation. Discussion: In patients with QAV and aortic stenosis undergoing TAVR, similar to the tricuspid valve, tomographic planning can be used to ensure the success of the procedure. However, unlike the tricuspid valve, where the selection of the device number is based on the measurements of the aortic annulus at the level of the non-coronary sinus, in these QAV cases, we perform the measurements at the level of the deepest aortic sinus (right coronary sinus).

Development and External Validation of Clinical Features-based Machine Learning Models for Predicting COVID-19 in the Emergency Department.

Introduction: Timely diagnosis of patients affected by an emerging infectious disease plays a crucial role in treating patients and avoiding disease spread. In prior research, we developed an approach by using machine learning (ML) algorithms to predict serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on clinical features of patients visiting an emergency department (ED) during the early coronavirus 2019 (COVID-19) pandemic. In this study, we aimed to externally validate this approach within a distinct ED population. Methods: To create our training/validation cohort (model development) we collected data retrospectively from suspected COVID-19 patients at a US ED from February 23-May 12, 2020. Another dataset was collected as an external validation (testing) cohort from an ED in another country from May 12-June 15, 2021. Clinical features including patient demographics and triage information were used to train and test the models. The primary outcome was the confirmed diagnosis of COVID-19, defined as a positive reverse transcription polymerase chain reaction test result for SARS-CoV-2. We employed three different ML algorithms, including gradient boosting, random forest, and extra trees classifiers, to construct the predictive model. The predictive performances were evaluated with the area under the receiver operating characteristic curve (AUC) in the testing cohort. Results: In total, 580 and 946 ED patients were included in the training and testing cohorts, respectively. Of them, 98 (16.9%) and 180 (19.0%) were diagnosed with COVID-19. All the constructed ML models showed acceptable discrimination, as indicated by the AUC. Among them, random forest (0.785, 95% confidence interval [CI] 0.747-0.822) performed better than gradient boosting (0.774, 95% CI 0.739-0.811) and extra trees classifier (0.72, 95% CI 0.677-0.762). There was no significant difference between the constructed models. Conclusion: Our study validates the use of ML for predicting COVID-19 in the ED and demonstrates its potential for predicting emerging infectious diseases based on models built by clinical features with temporal and spatial heterogeneity. This approach holds promise for scenarios where effective diagnostic tools for an emerging infectious disease may be lacking in the future.

Hafnium, Titanium, and Zirconium Intercalation in 2D Layered Nanomaterials.

Altering the physical and chemical properties of a layered material through intercalation has emerged as a unique strategy toward tunable applications. In this work, we demonstrate a wet chemical method to intercalate titanium, hafnium, and zirconium into 2D layered nanomaterials. The metals are intercalated using bis-tetrahydrofuran metal halide complexes. Metal intercalation is demonstrated in nanomaterials of Bi2Se3, Si2Te3, MoO3, and GeS. This strategy intercalates, on average, 3 atm % or less of Hf, Ti, and Zr that share charge with the host nanomaterial. This methodology is used to chemochromically alter MoO3 from transparent white to dark blue.

Encapsulation of ß-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair.

Introduction: Currently, there are no non-surgical FDA-approved biological approaches to accelerate fracture repair. Injectable therapies designed to stimulate bone healing represent an exciting alternative to surgically implanted biologics, however, the translation of effective osteoinductive therapies remains challenging due to the need for safe and effective drug delivery. Hydrogel-based microparticle platforms may be a clinically relevant solution to create controlled and localized drug delivery to treat bone fractures. Here, we describe poly (ethylene glycol) dimethacrylate (PEGDMA)-based microparticles, in the shape of microrods, loaded with beta nerve growth factor (ß-NGF) for the purpose of promoting fracture repair. Methods: Herein, PEGDMA microrods were fabricated through photolithography. PEGDMA microrods were loaded with ß-NGF and in vitro release was examined. Subsequently, bioactivity assays were evaluated in vitro using the TF-1 tyrosine receptor kinase A (Trk-A) expressing cell line. Finally, in vivo studies using our well-established murine tibia fracture model were performed and a single injection of the ß-NGF loaded PEGDMA microrods, non-loaded PEGDMA microrods, or soluble ß-NGF was administered to assess the extent of fracture healing using Micro-computed tomography (µCT) and histomorphometry. Results: In vitro release studies showed there is significant retention of protein within the polymer matrix over 168 hours through physiochemical interactions. Bioactivity of protein post-loading was confirmed with the TF-1 cell line. In vivo studies using our murine tibia fracture model show that PEGDMA microrods injected at the site of fracture remained adjacent to the callus for over 7 days. Importantly, a single injection of ß-NGF loaded PEGDMA microrods resulted in improved fracture healing as indicated by a significant increase in the percent bone in the fracture callus, trabecular connective density, and bone mineral density relative to soluble ß-NGF control indicating improved drug retention within the tissue. The concomitant decrease in cartilage fraction supports our prior work showing that ß-NGF promotes endochondral conversion of cartilage to bone to accelerate healing. Discussion: We demonstrate a novel and translational method wherein ß-NGF can be encapsulated within PEGDMA microrods for local delivery and that ß-NGF bioactivity is maintained resulting in improved bone fracture repair.

Parasitological and molecular detection of Trypanosoma evansi in a dog from Tocache, San Martin, Peru.

This study presents the first case report of canine trypanosomiasis caused by Trypanosoma evansi in Peru. The case was admitted to a veterinary clinic in the Peruvian Amazon region of San Martin with severe clinical symptomatology which resulted in the dog's death. Microscopy screening showed the presence of trypomastigotes in blood and bone marrow and postmortem histopathology found damage at the cardiac, lung, kidney and spleen levels. Collected specimens were tested by nested-PCR which were positive for Trypanosoma spp., but negative for T. cruzi. High-throughput sequencing determined that the infecting species was closely related to T. equiperdom/evansi and subsequent phylogenetic analysis confirmed that the sample was related to T. evansi. The presence of T. evansi in the area highlights the need for increased surveillance to assess the impact of surra in the region and to develop measures to prevent socioeconomic damage resulting from infections in domestic and farm animals as well as prevent zoonotic transmission.

Changes in Patient Reported Outcome Measure Scores From Initial Presentation to Day-of-Surgery in Patients Undergoing Hip and Knee Arthroplasty.

BACKGROUND: It is not well understood how patient reported outcome measures (PROMs) change from initial presentation to day-of-surgery (DOS). This study sought to quantify preoperative PROM changes for hip and knee arthroplasty patients. METHODS: A retrospective review was performed on primary total hip, total knee, and partial knee arthroplasty patients from October 2020 through January 2021. Trends in preoperative Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), Hip Disability and Osteoarthritis Outcome Score for Joint Replacement (HOOS-JR), and Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) scores were compared using scores at initial presentation in the ambulatory clinic and at a time near the date-of-surgery. A total of 497 patients possessed 2 preoperative PROMIS-PF (497/497), HOOS-JR (152/497), or KOOS-JR (258/497) surveys. RESULTS: There was no significant statistical difference in mean PROM scores between initial presentation and DOS PROMIS-PF or HOOS-JR scores. Only KOOS-JR demonstrated a significant statistical difference of 2 ± 14 (P = .002) when comparing initial versus preoperative scores. Partial knee arthroplasty patients saw a strong positive correlation (r = 0.77) between initial PROMIS-PF and DOS scores. However, mean absolute value changes on an individual level were 4 ± 4, 11 ± 39, and 11 ± 10 for PROMIS-PF, HOOS-JR, and KOOS-JR, respectively, indicating the presence of meaningful patient-level score changes as based on previously published anchor-based minimal clinically important differences. CONCLUSION: PROMs collected during the preoperative period demonstrated wide variability at an individual level, but not at a population level. Collection at both time points may be necessary in order to understand the clinical impact of surgery on these patients.

Comparison of Postoperative Instability and Acetabular Cup Positioning in Robotic-Assisted Versus Traditional Total Hip Arthroplasty.

BACKGROUND: Robotic-assisted total hip arthroplasty (R-THA) affords precision yet uncertain clinical benefits. This study compares dislocation rates and related revisions between R-THA and manual total hip arthroplasty (M-THA). Secondarily we evaluated cup position, patient-reported outcome measures (PROMs), and postoperative complications. METHODS: A three-surgeon cohort study was conducted on 2247 consecutive patients (1724 M-THA and 523 R-THA) who received a primary THA between January 2014 and June 2020 at a single hospital. Demographics, PROMs, emergency department visits, readmissions, and 90-day complications were collected via the Michigan Arthroplasty Registry Collaborative Quality Initiative. Chart review yielded instability occurrence with an average follow-up of 4 years. Multivariate regression analysis was performed, and a sample of 368 radiographs, including all dislocations, were assessed. RESULTS: There were significantly lower rates of dislocation in R-THA (0.6%) vs M-THA (2.5%; Multivariate odds ratio 3.74, P < .046). All cases of unstable R-THA were successfully treated conservatively, whereas 46% of unstable M-THA were revised for recurrent instability. Cup anteversion (25.6° ± 5.4° R-THA vs 20.6° ± 7.6° M-THA) was greater, and cup inclination (42.5° ± 5.3° R-THA vs 47.0° ± 6.7° M-THA) was lower in the R-THA group (P < .05). No significant differences were noted for demographics, PROMs, or other complications (P > .05). CONCLUSION: R-THA resulted in less than one-fourth the dislocation rate compared to M-THA and no revision for instability. It was associated with no difference in PROMs or other early complications. The influence of R-THA on stability goes beyond simply cup positioning and deserves further study.

Concussions in the National Hockey League: Analysis of Incidence, Return to Play, and Performance.

BACKGROUND: Concussion injuries are common in professional hockey; however, their effect on player performance remains unclear. PURPOSE: To quantify the effect of concussions on the performance of position players in the National Hockey League (NHL). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Concussion data from the NHL were collected using publicly available databases for the seasons between 2009-2010 and 2015-2016, coinciding with new NHL concussion rules. Age, body mass index, position, number of concussions during a player's NHL career, games played, and time on ice were recorded. Basic and advanced performance metrics were collected for 1 season pre- and postconcussion (short-term period) and 3 seasons before and after concussion (long-term period) to assess short- and long-term changes in performance. A control group of players without an identified concussion who competed during the study period was assembled for comparison. Wilcoxon signed rank tests were used to evaluate pre- to postconcussion data in the short- and long-term settings as well as to compare the cohorts at each time point. RESULTS: Overall, 48 players were identified as having a concussion during the study period. Players missed 17.2 ± 15.1 days (mean ± standard deviation) and 7.5 ± 6.9 games postconcussion. There were no significant differences in any metric when pre- and postconcussion intraseason performance was assessed. Athletes who were concussed demonstrated significantly deceased performance metrics (assists per 60 minutes, points per 60 minutes, Corsi percentage, and Fenwick percentage) in the 3 years after the concussion as compared with the year before injury (P < .05). However, no difference was found between the concussed group and matched control group in the short- or long-term period. Players with concussion played fewer career games (856.4 ± 287.4 vs 725.7 ± 215.0; P < .05) than did controls. CONCLUSION: A high rate of NHL players were able to return to play after a concussion injury. Players with concussion did not experience a reduction in performance metrics in the short- or long-term setting when compared with matched controls. The concussed cohort maintained a similar workload up to 3 seasons postconcussion but played in fewer career games when compared with matched controls.

Estudio descriptivo del perfil de investigadoras hondureñas en Google Académico / Descriptive study of the profile of Honduran female researchers in Google Scholar

Introducción: El rol de la mujer en el área científica ha crecido con el paso de los años, pero aún persiste una gran brecha de género en ciencia. Para conocer y manejar esa brecha, es necesario hacer un mapeo de la situación de las mujeres investigadoras en Honduras. Objetivo: Describir la participación y contribuciones de las investigadoras hondureñas en la producción científica nacional según su perfil en Google Académico. Metodología: Se usó Power BI para analizar las variables sexo, institución, índice H, número de citaciones, número de publicaciones, año de la primera publicación, y áreas de investigación registradas en su perfil, utilizando la versión 2 del Ranking de Investigadores Hondureños según su Perfil de Google Académico disponible en https://bit.ly/38s6YuT, el cual es un registro depurado. Resultados: El 35% de todos los perfiles eran de mujeres, 41% vinculadas a las ciencias médicas y de la salud y en su mayoría (92%), afiliadas a universidades. Pese al creciente número de mujeres investigadoras registradas en Google Académico, el crecimiento no es simétrico respecto a los hombres. Solamente el 3.1% de las investigadoras tenía un índice H que supera los dos dígitos. Conclusión: A pesar de los avances, se mantiene la inequidad de género entre investigadores hondureños según la data de Google Académico. Se requiere de políticas públicas e institucionales, para corregir esa brecha...(AU)

Game Utilization and Performance Following RTP From ACL Reconstruction Does not Influence a Subsequent Second ACL Injury in National Football League Players.

PURPOSE: The purpose of this study is to evaluate differences in game utilization or performance following primary anterior cruciate ligament (ACL) reconstruction between National Football League (NFL) players with and without a second ACL injury. METHODS: NFL players who underwent ACL reconstruction between 2013 and 2017 were identified. Players were classified as having one injury ("tear") or having later sustained a subsequent second (reinjury or contralateral) ACL injury ("retear"). Players were excluded if they tore their ACL prior to the NFL, did not return to play (RTP), did not play the season before injury, or had concomitant injuries. Demographic characteristics, game utilization statistics, and season approximate value (SAV) performance metrics were recorded. Statistical analysis compared data after RTP from primary ACL reconstruction (seasons +1, +2, and +3) relative to the season before injury (season -1) between cohorts using mean differences and relative percentages. RESULTS: Analysis included a total of 45 players, 32 in the "tear" group and 13 in the "retear" group. Demographics, level of play, and time to RTP after primary ACL reconstruction did not differ between the groups (P > .05). Tear and retear groups demonstrated similar utilization and performance metrics the season prior to injury (-1) and the 3 seasons following RTP (season of injury is "0"). Both groups had a similar decrease (relative percentage) in games played and started, snap counts, and SAV during the 3 seasons following RTP compared to baseline (P > .05). The draft pick position was correlated with the relative percentage of games started the first season after RTP (r = .6, P = .02). CONCLUSIONS: Game utilization and performance metrics following ACL reconstruction were not associated with a subsequent second ACL injury. Players with a higher draft pick position were more likely to return to the starting lineup following primary ACL reconstruction. Ultimately, player game utilization and performance following primary ACL reconstruction is not predictive of a subsequent second ACL injury. LEVEL OF EVIDENCE: Level III, retrospective case-control study.

A Narrative Review of Mental Illness Stigma Reduction Interventions Among African Americans in The United States.

Among African Americans, the chronicity and severity of mental illness correlates with worse health outcomes and widens health disparities. Stigma related to mental illness compounds mental health disparities by creating barriers to help-seeking behavior. We examine the current tools designed to reduce mental illness stigma and promote improved mental health outcomes among African Americans. The authors reviewed the current evidence in the literature for such stigma reduction interventions. The review team developed a focused search across four databases: PubMed, Embase, Scopus, and APA PsycINFO. Initial searches identified 120 articles, from which six studies were included as reporting on mental illness stigma reduction interventions among African Americans. We describe these four quantitative and two qualitative studies. There have been various interventions used among African Americans to reduce mental illness stigma, and the level of efficacy and effectiveness is not well studied. Our review demonstrated a need for more robust studies to yield strong evidence on effectiveness among stigma reduction interventions in this target population. The evidence does support tailoring intervention studies to this population. Effectively engaging and partnering with key stakeholders, including schools, community organizations, and faith-based institutions enhances the acceptance and delivery of stigma reduction interventions.

Reducing Antisolvent Use in the STRAP Process by Enabling a Temperature-Controlled Polymer Dissolution and Precipitation for the Recycling of Multilayer Plastic Films.

The recently reported processing strategy called solvent-targeted recovery and precipitation (STRAP) enables deconstruction of multilayer plastic packaging films into their constituent resins by selective dissolution. It uses a series of solvent washes that are guided by thermodynamic calculations of polymer solubility. In this work, the use of antisolvents in the STRAP process was reduced and solvent mixtures were considered to enable the temperature-controlled dissolution and precipitation of the target polymers in multilayer films. This was considered as a means to further improve the STRAP process and its estimated costs. Two STRAP approaches were compared based on different polymer precipitation techniques: precipitation by the addition of an antisolvent (STRAP-A) and precipitation by decreasing the solvent temperature (STRAP-B). Both approaches were able to separate the constituent polymers in a post-industrial film composed primarily of polyethylene (PE), ethylene vinyl alcohol (EVOH), and polyethylene terephthalate (PET) with near 100 % material efficiency. Technoeconomic analysis indicates that the minimum selling price (MSP) of the recycled resins with STRAP-B is 21.0 % lower than that achieved with STRAP-A. This provides evidence that thermally driven polymer precipitation is an option to reduce the use of antisolvents, making the STRAP process more economically and environmentally attractive. A third process, STRAP-C, was demonstrated with another post-industrial multilayer film of a different composition. The results demonstrate that this process can also recover polymers at similar costs to those of virgin resins, indicating that the STRAP technology is flexible and can remain economically competitive as the plastic feed complexity is increased.

Natural and Synthetic Cannabinoids: Pharmacology, Uses, Adverse Drug Events, and Drug Interactions.

The purpose of this narrative review is to describe the current use environment of both natural and synthetic cannabinoids while providing context for cannabinoid chemistry and pharmacology. In addition to a long history of recreational and nonmedical use, natural cannabinoids are increasingly used as prescription products, through medical cannabis programs, and as consumer health products. Despite anecdotal safety evidence, cannabis and cannabinoids are pharmacologically complex and pose risks for adverse drug events and drug-drug interactions. Synthetic cannabinoids, particularly agonists of cannabinoid receptors, are more potent than natural cannabinoids and can lead to more severe reactions and medical emergencies. This review provides a summary of approved uses and an overview of mechanisms of action for adverse drug events with natural and synthetic cannabinoids. Clinical considerations for special populations that may be at heightened risk for drug-drug interactions and adverse drug events while using natural or synthetic cannabinoids are examined, and recommendations are provided.

Computational Approach for Rapidly Predicting Temperature-Dependent Polymer Solubilities Using Molecular-Scale Models.

One promising approach to recycle multicomponent plastic waste (e. g., multilayer plastic films) is selective dissolution. Selective dissolution is a solvent-mediated process in which differences in polymer solubility in a carefully chosen solvent system are exploited to recover a target polymer. Here, a computational approach was developed that rapidly predicts temperature-dependent polymer solubilities to guide the design of solvent systems for solvent-mediated polymer recycling. Polymer conformations were obtained from molecular dynamics simulations by modeling the polymer as a short oligomer and then used as input to the conductor-like screening model for real solvents (COSMO-RS) for solubility predictions. Using polyethylene (PE) and ethylene vinyl alcohol (EVOH) as representative polymers, the effect of simulation parameters was systematically studied, and predicted solubilities were found to be in good agreement with experimental measurements. The applicability of the approach was demonstrated by identifying selective solvents for PE and EVOH dissolution from a library of 524 solvents.

The Diagnostic Challenge of the Pediatric Brain Abscess.

Pediatric brain abscess (PBA) is a rare condition that portends a high mortality rate if not recognized and treated early. The spectrum of clinical manifestations of this disease process is wide and can often be vague, making it difficult for timely diagnosis in the emergency department. We detail the presentation of a four-year-old male with autism and a four-day history of decreased activity after a fall with a critical and rapidly worsening clinical course. Subsequent operative intervention revealed a diagnosis of PBA. This case highlights the clinical challenges of diagnosing altered mental status in a developmentally challenged pediatric patient.

Point-of-Care Ultrasound Diagnosis of a Crohn's Disease-Related Intraabdominal Abscess in the Emergency Department.

The emergency department (ED) diagnosis of Crohn's disease (CD)-associated complications is typically established with abdominopelvic computed tomography imaging. Ultrasonography has been suggested as an effective alternative modality for diagnosing several CD complications, including intraabdominal abscesses. We report the identification of a CD-related intraabdominal abscess by emergency physician (EP)-performed point-of-care ultrasound (POCUS). This case highlights the feasibility of EPs integrating POCUS into the clinical decision-making for patients with inflammatory bowel disease in the ED.

Hepatectomy, RFA, and Other Liver Directed Therapies for Treatment of Breast Cancer Liver Metastasis: A Systematic Review.

BACKGROUND: The liver is the second most common site of breast cancer metastasis. Liver directed therapies including hepatic resection, radiofrequency ablation (RFA), transarterial chemo- and radioembolization (TACE/TARE), and hepatic arterial infusion (HAI) have been scarcely researched for breast cancer liver metastasis (BCLM). The purpose of this review is to present the known body of literature on these therapies for BCLM. METHODS: A systematic review was performed with pre-specified search terms using PubMed, MEDLINE, EMBASE, and Cochrane Review resulting in 9,957 results. After review of abstracts and application of exclusion criteria, 51 studies were included in this review. RESULTS: Hepatic resection afforded the longest median overall survival (mOS) and 5-year survival (45 mo, 41%) across 23 studies. RFA was presented in six studies with pooled mOS and 5-year survival of 38 mo and 11-33%. Disease burden and tumor size was lower amongst hepatic resection and RFA patients. TACE was presented in eight studies with pooled mOS and 1-year survival of 19.6 mo and 32-88.8%. TARE was presented in 10 studies with pooled mOS and 1-year survival of 11.5 mo and 34.5-86%. TACE and TARE populations were selected for chemo-resistant, unresectable disease. Hepatic arterial infusion was presented in five studies with pooled mOS of 11.3 months. CONCLUSION: Although further studies are necessary to delineate appropriate usage of liver directed therapies in BCLM, small studies suggest hepatic resection and RFA, in well selected patients, can result in prolonged survival. Longitudinal studies with larger cohorts are warranted to further investigate the effectiveness of each modality.

Minimal Clinically Important Difference in Robotic-Assisted Total Knee Arthroplasty Versus Standard Manual Total Knee Arthroplasty.

BACKGROUND: The purpose of this study was to determine whether robotic total knee arthroplasty (R-TKA) demonstrated evidence of improvement in minimal clinically important difference (MCID) in early (<4 weeks) and intermittent (4-8 month) patient-reported outcomes compared with manual total knee arthroplasty (M-TKA). METHODS: A prospectively collected database was reviewed of 1160 consecutive patients undergoing R-TKA or M-TKA from December 2017 to October 2019. Primary outcomes consisted of Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR) and Patient-Reported Outcomes Measurement Information System Global Health Measures of Physical Health (PH) and Mental Health (MH). Statistical analysis included MCID via the distribution method. RESULTS: Univariate analysis demonstrated conflicting results for early MCID achievement favoring M-TKA (4-week KOOS-JR, P = .03) for the multisurgeon cohort, but favored R-TKA (4-week Patient-Reported Outcomes Measurement Information System-PH, P = .04) in the single-surgeon analysis, and the remaining outcome scores were similar. Ultimately, multivariate analysis demonstrated similar 4-week and 6-month MCID achievement in all measures. Lower preoperative scores consistently achieved MCID at a higher rate in M-TKA, although in R-TKA, the higher baseline scores improved at a rate comparable with those with lower scores in all but the short-term postoperative KOOS-JR. CONCLUSION: R-TKA demonstrated comparable MCID achievement to M-TKA across the larger cohort. Single-surgeon comparison did show some early benefit. Confounding variables such as surgical technique, implant fixation, and responsiveness of an outcome measure may be as important as simply what tools are used during surgery. Such granular data should be sought out in future studies.

Local injections of ß-NGF accelerates endochondral fracture repair by promoting cartilage to bone conversion.

There are currently no pharmacological approaches in fracture healing designed to therapeutically stimulate endochondral ossification. In this study, we test nerve growth factor (NGF) as an understudied therapeutic for fracture repair. We first characterized endogenous expression of Ngf and its receptor tropomyosin receptor kinase A (TrkA) during tibial fracture repair, finding that they peak during the cartilaginous phase. We then tested two injection regimens and found that local ß-NGF injections during the endochondral/cartilaginous phase promoted osteogenic marker expression. Gene expression data from ß-NGF stimulated cartilage callus explants show a promotion in markers associated with endochondral ossification such as Ihh, Alpl, and Sdf-1. Gene ontology enrichment analysis revealed the promotion of genes associated with Wnt activation, PDGF- and integrin-binding. Subsequent histological analysis confirmed Wnt activation following local ß-NGF injections. Finally, we demonstrate functional improvements to bone healing following local ß-NGF injections which resulted in a decrease in cartilage and increase of bone volume. Moreover, the newly formed bone contained higher trabecular number, connective density, and bone mineral density. Collectively, we demonstrate ß-NGF's ability to promote endochondral repair in a murine model and uncover mechanisms that will serve to further understand the molecular switches that occur during cartilage to bone transformation.