Robotic-Assisted Total Knee Arthroplasty Has Similar Rates of Prosthetic Noise Generation as Conventional Total Knee Arthroplasty.

Background: Noise has been reported to occur with relatively high frequency after conventional total knee arthroplasty (C-TKA), and this may impact the incidence of patient satisfaction and function. The purpose of this study was to compare the rate of patient-reported prosthetic noise generation after robotically-assisted TKA (RA-TKA) and C-TKA. Methods: A retrospective study was conducted of unilateral primary RA-TKAs and C-TKAs performed between 2018 and 2021. Patients completed a survey consisting of 4 Likert scale questions related to prosthetic noise generation and Knee Injury and Osteoarthritis Score Joint Replacement and Forgotten Joint Score were assessed prospectively preoperatively and at a minimum of 1-year of clinical follow-up. Statistical analysis was done utilizing T-tests and chi-square tests, with statistical significance defined as a P-value < .05. Results: One hundred sixty-two RA-TKAs and 320 C-TKAs with similar baseline characteristics and functions were included. There were no significant differences in hearing or feeling grinding, popping, clicking, or clunking (40.7% vs 38.1%; P = .647) between groups. Most RA-TKAs and C-TKAs were not dissatisfied regarding noise generation (70.4% vs 73.1%; P = .596). In both cohorts, patients who reported noise generation had lower average Forgotten Joint Scores (45.5 vs 66.1; P < .001) and lower postoperative Knee Injury and Osteoarthritis Score Joint Replacement scores (72.0 vs 81.4; P < .001) than those who did not experience noise generation. Conclusions: While RA-TKA may facilitate soft tissue balancing, there were no differences in prosthetic noise generation between RA-TKA and C-TKA. However, those who experience implant-generated noise have lower functional outcome scores.

Making a Joint Decision Regarding the Timing of Surgery for Elective Arthroplasty Surgery After Being Infected With COVID-19: A Systematic Review.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has caused a substantial number of patients to have their elective arthroplasty surgeries rescheduled. While it is established that patients with COVID-19 who are undergoing surgery have a significantly higher risk of experiencing postoperative complications and mortality, it is not well-known at what time after testing positive the risk of postoperative complications or mortality returns to normal. METHODS: PubMed (MEDLINE), Excerpta Medica dataBASE, and professional society websites were systematically reviewed on March 7, 2022 to identify studies and guidelines on the optimal timeframe to reschedule patients for elective surgery after preoperatively testing positive for COVID-19. Outcomes included postoperative complications such as mortality, pneumonia, acute respiratory distress syndrome, septic shock, and pulmonary embolism. RESULTS: A total of 14 studies and professional society guidelines met the inclusion criteria for this systematic review. Patients with asymptomatic COVID-19 should be rescheduled 4-8 weeks after testing positive (as long as they do not develop symptoms in the interim), patients with mild/moderate COVID-19 should be rescheduled 6-8 weeks after testing positive (with complete resolution of symptoms), and patients with severe/critical COVID-19 should be rescheduled at a minimum of 12 weeks after hospital discharge (with complete resolution of symptoms). CONCLUSIONS: Given the negative association between preoperative COVID-19 and postoperative complications, patients should have elective arthroplasty surgery rescheduled at differing timeframes based on their symptoms. In addition, a multidisciplinary and patient-centered approach to rescheduling patients is recommended. Further study is needed to examine the impact of novel COVID-19 variants and vaccination on timeframes for rescheduling surgery.

Virtual Reality as a Learning Tool for Trainees in Unicompartmental Knee Arthroplasty: A Randomized Controlled Trial.

INTRODUCTION: The efficacy of virtual reality (VR) as a teaching augment for arthroplasty has not been well examined for unfamiliar multistep procedures such as unicompartmental knee arthroplasty (UKA). This study sought to determine whether VR improves surgical competence over traditional procedural preparation when performing a UKA. METHODS: Twenty-two orthopaedic surgery trainees were randomized to two surgical preparation cohorts: (1) "Guide" group (control) with access to manufacture's technique guide and surgical video and (2) "VR" group with access to an immersive commercially available VR learning module. Surgical performance of UKA on a SawBone model was assessed through time and the Objective Structured Assessment of Technical Skills (OSATS) validated rating system. RESULTS: Participants were equally distributed among all training levels and previous exposure to UKA. No difference in mean surgical times was observed between Guide and VR groups (Guide = 42.4 minutes versus VR = 43.0 minutes; P = 0.9) or mean total OSATS (Guide = 15.7 versus VR = 14.2; P = 0.59). Most trainees felt VR would be a useful tool for resident education (77%) and would use VR for case preparation if available (86.4%). CONCLUSION: In a randomized controlled trial of trainees at a single, large academic center performing a complex, multistep, unfamiliar procedure (UKA), VR training demonstrated equivalent surgical competence compared with the use of traditional technique guides, as measured by surgical time and OSATS scores. Most of the trainees found the VR technology beneficial. This study suggests that VR technology may be considered as an adjunct to traditional surgical preparation/training methods.

Radiographic shoulder parameters and their relationship to outcomes following rotator cuff repair: a systematic review.

BACKGROUND: Anatomic parameters, such as the critical shoulder angle and acromion index, have emerged as methods to quantify scapular anatomy and may contribute to rotator cuff pathology. The purpose of this paper is to investigate the published literature on influences of scapular morphology on the development of re-tears and patient-reported outcomes following rotator cuff repair. METHODS: A systematic review of the Embase and PubMed databases was performed to identify published studies on the potential influence of scapular bony morphology and re-tear rates and patient-reported outcomes after rotator cuff repair. Studies were reviewed by two authors. RESULTS: A total of 615 unique titles and 49 potentially relevant abstracts were reviewed, with eight published manuscripts identified for inclusion. Two of three papers reported no relationship between these acromion index and rotator cuff re-tear rate, while one paper found an increased re-tear rate. All three studies on critical shoulder angle found a significant association between critical shoulder angle and cuff re-tear rate. There was no clear relationship between any bony morphologic measurement and patient-reported outcomes after rotator cuff repair. CONCLUSIONS: Rotator cuff re-tear rate appears to be significantly associated with the critical shoulder angle and glenoid inclination, while not clearly associated with acromial morphologic measurements.

Automatic Hip Fracture Identification and Functional Subclassification with Deep Learning.

PURPOSE: To investigate the feasibility of automatic identification and classification of hip fractures using deep learning, which may improve outcomes by reducing diagnostic errors and decreasing time to operation. MATERIALS AND METHODS: Hip and pelvic radiographs from 1118 studies were reviewed, and 3026 hips were labeled via bounding boxes and classified as normal, displaced femoral neck fracture, nondisplaced femoral neck fracture, intertrochanteric fracture, previous open reduction and internal fixation, or previous arthroplasty. A deep learning-based object detection model was trained to automate the placement of the bounding boxes. A Densely Connected Convolutional Neural Network (or DenseNet) was trained on a subset of the bounding box images, and its performance was evaluated on a held-out test set and by comparison on a 100-image subset with two groups of human observers: fellowship-trained radiologists and orthopedists; senior residents in emergency medicine, radiology, and orthopedics. RESULTS: The binary accuracy for detecting a fracture of this model was 93.7% (95% confidence interval [CI]: 90.8%, 96.5%), with a sensitivity of 93.2% (95% CI: 88.9%, 97.1%) and a specificity of 94.2% (95% CI: 89.7%, 98.4%). Multiclass classification accuracy was 90.8% (95% CI: 87.5%, 94.2%). When compared with the accuracy of human observers, the accuracy of the model achieved an expert-level classification, at the very least, under all conditions. Additionally, when the model was used as an aid, human performance improved, with aided resident performance approximating unaided fellowship-trained expert performance in the multiclass classification. CONCLUSION: A deep learning model identified and classified hip fractures with expert-level performance, at the very least, and when used as an aid, improved human performance, with aided resident performance approximating that of unaided fellowship-trained attending physicians.Supplemental material is available for this article.© RSNA, 2020.

Machine Learning Algorithms Can Use Wearable Sensor Data to Accurately Predict Six-Week Patient-Reported Outcome Scores Following Joint Replacement in a Prospective Trial.

BACKGROUND: Tracking patient-generated health data (PGHD) following total joint arthroplasty (TJA) may enable data-driven early intervention to improve clinical results. We aim to demonstrate the feasibility of combining machine learning (ML) with PGHD in TJA to predict patient-reported outcome measures (PROMs). METHODS: Twenty-two TJA patients were recruited for this pilot study. Three activity trackers collected 35 features from 4 weeks before to 6 weeks following surgery. PROMs were collected at both endpoints (Hip and Knee Disability and Osteoarthritis Outcome Score, Knee Osteoarthritis Outcome Score, and Veterans RAND 12-Item Health Survey Physical Component Score). We used ML to identify features with the highest correlation with PROMs. The algorithm trained on a subset of patients and used 3 feature sets (A, B, and C) to group the rest into one of the 3 PROM clusters. RESULTS: Fifteen patients completed the study and collected 3 million data points. Three sets of features with the highest R2 values relative to PROMs were selected (A, B and C). Data collected through the 11th day had the highest predictive value. The ML algorithm grouped patients into 3 clusters predictive of 6-week PROM results, yielding total sum of squares values ranging from 3.86 (A) to 1.86 (C). CONCLUSION: This small but critical proof-of-concept study demonstrates that ML can be used in combination with PGHD to predict 6-week PROM data as early as 11 days following TJA surgery. Further study is needed to confirm these findings and their clinical value.

Optimal Sampling Frequency for Wearable Sensor Data in Arthroplasty Outcomes Research. A Prospective Observational Cohort Trial.

BACKGROUND: Wearable sensors can track patient activity after surgery. The optimal data sampling frequency to identify an association between patient-reported outcome measures (PROMs) and sensor data is unknown. Most commercial grade sensors report 24-hour average data. We hypothesize that increasing the frequency of data collection may improve the correlation with PROM data. METHODS: Twenty-two total joint arthroplasty (TJA) patients were prospectively recruited and provided wearable sensors. Second-by-second (Raw) and 24-hour average data (24Hr) were collected on 7 gait metrics on the 1st, 7th, 14th, 21st, and 42nd days postoperatively. The average for each metric as well as the slope of a linear regression for 24Hr data (24HrLR) was calculated. The R2 associations were calculated using machine learning algorithms against individual PROM results at 6 weeks. The resulting R2 values were defined having a mild, moderate, or strong fit (R2 ≥ 0.2, ≥0.3, and ≥0.6, respectively) with PROM results. The difference in frequency of fit was analyzed with the McNemar's test. RESULTS: The frequency of at least a mild fit (R2 ≥ 0.2) for any data point at any time frame relative to either of the PROMs measured was higher for Raw data (42%) than 24Hr data (32%; P = .041). There was no difference in frequency of fit for 24hrLR data (32%) and 24Hr data values (32%; P > .05). Longer data collection improved frequency of fit. CONCLUSION: In this prospective trial, increasing sampling frequency above the standard 24Hr average provided by consumer grade activity sensors improves the ability of machine learning algorithms to predict 6-week PROMs in our total joint arthroplasty cohort.

Preoperative IDEAL (Iterative Decomposition of Echoes of Asymmetrical Length) magnetic resonance imaging rotator cuff muscle fat fractions are associated with rotator cuff repair outcomes.

BACKGROUND AND HYPOTHESIS: IDEAL (Iterative Decomposition of Echoes of Asymmetrical Length) imaging is a magnetic resonance imaging sequence that precisely measures rotator cuff muscle fatty infiltration. The influence of lower levels of fatty infiltration on outcomes after rotator cuff repair remains unclear. We hypothesized that increased preoperative fat fractions would be associated with inferior clinical outcomes after rotator cuff repair. METHODS: We retrospectively identified patients who underwent arthroscopic rotator cuff repair with preoperative IDEAL imaging. Patients completed the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity computer adaptive survey at a minimum of 2 years after repair. Muscle segmentation was performed on 4 consecutive slices. Correlations between intramuscular fat fractions and PROMIS scores were determined. Patients were grouped by PROMIS scores of 50 or greater and scores lower than 50 for comparison of fat fractions. Multivariate linear regression was performed to model PROMIS scores as a function of demographic characteristics, tear size, and fat fractions. Significance was defined as P < .05. RESULTS: Eighty patients were included (mean follow-up, 42.5 ± 10.7 months). Postoperative PROMIS scores were significantly inversely correlated with the infraspinatus (ρ = -0.25, P = .02) and subscapularis (ρ = -0.29, P = .009) fat fractions. The infraspinatus (7.2% ± 4.9% vs. 5.2% ± 3.0%, P = .046) and subscapularis (10.4% ± 5.1% vs. 8.2% ± 5.0%, P = .001) fat fractions were significantly higher for patients with low PROMIS scores vs. those with PROMIS scores of 50 or greater. In multivariate modeling, the infraspinatus fat fraction (ß = -0.68, P = .029) was the only significant independent predictor of postoperative PROMIS score. CONCLUSION: Intramuscular fat as determined by quantitative magnetic resonance imaging is an important factor in postoperative outcomes even in patients with lower levels of preoperative fatty infiltration.

Anatomic shoulder parameters and their relationship to the presence of degenerative rotator cuff tears and glenohumeral osteoarthritis: a systematic review and meta-analysis.

BACKGROUND: Scapular anatomy, as measured by the acromial index (AI), critical shoulder angle (CSA), lateral acromial angle (LAA), and glenoid inclination (GI), has emerged as a possible contributor to the development of degenerative shoulder conditions such as rotator cuff tears and glenohumeral osteoarthritis. The purpose of this study was to investigate the published literature on influences of scapular morphology on the development of degenerative shoulder conditions. METHODS: A systematic review of the Embase and PubMed databases was performed to identify published studies on the potential influence of scapular bony morphology on the development of degenerative rotator cuff tears and glenohumeral osteoarthritis. The studies were reviewed by 2 authors. The findings were summarized for various anatomic parameters. A meta-analysis was completed for parameters reported in more than 5 related publications. RESULTS: A total of 660 unique titles and 55 potentially relevant abstracts were reviewed with 30 published articles identified for inclusion. The AI, CSA, LAA, and GI were the most commonly reported bony measurements. Increased CSA and AI correlated with rotator cuff tears, whereas lower CSA appeared to be related to the presence of glenohumeral osteoarthritis. Decreased LAA correlated with degenerative rotator cuff tears. Five articles reported on the GI with mixed results on shoulder pathology. DISCUSSION: Degenerative rotator cuff tears appear to be significantly associated with the AI, CSA, and LAA. There does not appear to be a significant relationship between the included shoulder parameters and the development of osteoarthritis.

Orthopaedic Osseointegration: State of the Art.

Osseointegration is a surgical approach that permitted the direct attachment of an external prosthesis to the skeleton in some select patients with amputation, who had failed to tolerate conventional sockets, thereby obviating related issues such as discomfort, skin breakdown, and poor fit. In this specific population, osseointegration offers the potential for enhanced biomechanical advantage and rehabilitative potential. Multiple percutaneous implant systems exist for clinical use internationally, each attempting to create a stable bone-implant interface while avoiding complications such as infection and loosening. Prospective clinical trials are now underway in the United States. This article will review the history and biology of osseointegration, indications and contraindications for use of currently available implant systems, and reported outcomes. Future directions of orthopaedic osseointegration technology, including electronic systems capable of biomimetic bidirectional volitional motor control of, and sensory/proprioceptive feedback from, external prosthetic devices, will also be discussed.

Cutibacterium (formerly Propionibacterium) acnes clavicular infection.

Cutibacterium (formerly Propionibacterium) acnes13, 16 is a slow growing, gram-positive bacteria that is naturally found in higher concentrations as skin flora on the chest and back, as well as in other areas with greater numbers of hair follicles.25, 37 Most of the reported cases of C. acnes shoulder girdle infection follow arthroplasty surgery,18, 20, 26, 27, 32, 35 which then often requires debridement, administration of intravenous antibiotics, and surgical revision of the implanted device.12, 15, 21, 28-30 In a recent study, 56% of 193 shoulder revisions had a positive culture, 70% of which grew C. acnes.30 Despite the relatively common presumed association of C. acnes humeral osteomyelitis with prosthetic infection, infection of the scapula or clavicle secondary to C. acnes is rare.4, 23, 36 Osteomyelitis of the clavicle involving any organism is also an uncommon event that can arise spontaneously via presumed hematogenous spread, or secondary to open fractures or internal fixation.6, 33 The most commonly found organism in clavicular osteomyelitis is Staphylococcus aureus.9 We here report two cases of clavicular infection secondary to C. acnes that were not associated with implants.

Variations in Knee Kinematics After ACL Injury and After Reconstruction Are Correlated With Bone Shape Differences.

BACKGROUND: The factors that contribute to the abnormal knee kinematics after anterior cruciate ligament (ACL) injury and ACL reconstruction remain unclear. Bone shape has been implicated in the development of hip and knee osteoarthritis, although there is little knowledge about the effects of bone shape on knee kinematics after ACL injury and after ACL reconstruction. QUESTIONS/QUESTIONS: (1) What is the relationship between bony morphology with alterations in knee kinematics after ACL injury? (2) Are baseline bone shape features related to abnormal knee kinematics at 12 months after ACL reconstruction? METHODS: Thirty-eight patients (29 ± 8 years, 21 men) were prospectively followed after acute ACL injury and before ligamentous reconstruction. Patients were excluded if there was a history of prior knee ligamentous injury, a history of inflammatory arthritis, associated meniscal tears that would require repair, or any prior knee surgery on either the injured or contralateral side. In total, 54 patients were recruited with 42 (78%) patients completing 1-year followup and four patients excluded as a result of incomplete or unusable imaging data. MR images were obtained for the bilateral knees at two time points 1 year apart for both the injured (after injury but before reconstruction and 1 year after reconstruction) and contralateral uninjured knees. Kinematic MRI was performed with the knee loaded with 25% of total body weight, and static images were obtained in full extension and in 30° of flexion. The side-to-side difference (SSD) between tibial position in the extended and flexed positions was determined for each patient. Twenty shape features, referred to as modes, for the tibia and femur each were extracted independently from presurgery scans with the principal component analysis-based statistical shape modeling algorithm. Spearman rank correlations were used to evaluate the relationship between the SSD in tibial position and bone shape features with significance defined as p < 0.05. Each of the shape features (referred to as the bone and mode number such as Femur 18 for the 18th unique femoral bone shape) associated with differences in tibial position was then investigated by modeling the mean shape ± 3 SDs. RESULTS: Two of the 20 specific femur bone shape features (Femur 10, Femur 18) and two of the 20 specific tibial bone shape features (Tibia 19, Tibia 20) were associated with an increasingly anterior SSD in the tibial position for the patients with ACL injury before surgical treatment. The shape features described by these modes include the superoinferior height of the medial femoral condyle (Femur 18; ρ = 0.33, p = 0.040); the length of the anterior aspect of the lateral tibial plateau (Tibia 20; ρ = -0.35, p = 0.034); the sphericity of the medial femoral condyle (Femur 10; ρ = -0.52, p < 0.001); and tibial slope (Tibia 19; ρ = 0.34; p = 0.036). One year after surgical treatment, there were two of 20 femoral shape features that were associated with SSD in the tibial position in extension (Femur 10, Femur 18), one of 20 femoral shape features associated with SSD in the tibial position in flexion (Femur 10), and three of 20 tibial shape features associated with SSD in the tibial position in flexion (Tibia 2, Tibia 4, Tibia 19). The shape features described by these modes include the sphericity of the medial femoral condyle (Femur 10; ρ = -0.38, p = 0.020); the superoinferior height of the medial femoral condyle (Femur 18; ρ = 0.34, p = 0.035); the height of the medial tibial plateau (Tibia 2; ρ = -0.32, p = 0.048); the AP length of the lateral tibial plateau (Tibia 4; ρ = -0.37, p = 0.021); and tibial slope (Tibia 19; ρ = 0.34, p = 0.038). CONCLUSIONS: We have observed multiple bone shape features in the tibia and the femur that may be associated with abnormal knee kinematics after ACL injury and ACL reconstruction. Future directions of research will include the influence of bony morphology on clinical symptoms of instability in patients with and without ACL reconstruction and the long-term evaluation of these shape factors to better determine specific contributions to posttraumatic arthritis and graft failure. LEVEL OF EVIDENCE: Level II, therapeutic study.

A comprehensive in vivo kinematic, quantitative MRI and functional evaluation following ACL reconstruction--A comparison between mini-two incision and anteromedial portal femoral tunnel drilling.

BACKGROUND: Multiple techniques are used for femoral tunnel drilling in ACL reconstruction, including the Mini-two Incision Method (MT) and Anteromedial Portal Technique (AM). Both techniques allow for independent placement of the femoral tunnel, though there are no reports comparing kinematics and cartilage health after these reconstructions. We hypothesized that both techniques would result in the restoration of normal knee kinematics and show no evidence of early cartilage degeneration. METHODS: A total of 20 patients were evaluated one year after ACL reconstruction, including 10 patients after MT and 10 patients after AM. MR-imaging was acquired bilaterally with the knee loaded in extension and flexion to evaluate the kinematics of the reconstructed knee compared with the normal knee. Quantitative cartilage imaging was obtained and compared with 10 matched control subjects. The Marx Activity Rating Scale and KOOS survey were administered. RESULTS: The tibia was positioned significantly more anteriorly in extension and flexion relative to the contralateral knee for the MT group. The tibial position in the AM group was not significantly different from the patient's contralateral knee. T1ρ values in the central-medial tibia were significantly elevated in the MT group compared with the Control group. KOOS Symptom scores were significantly better for the MT group compared with the AM group. CONCLUSIONS: We have observed in vivo differences in knee kinematics and early cartilage degeneration between patients following MT and AM ACL reconstructions. Both techniques allow for anatomic ACL reconstruction, though the MT group shows significant early differences compared with the patient's normal knee.

Abnormal tibial position is correlated to early degenerative changes one year following ACL reconstruction.

Altered knee kinematics following ACL reconstruction may predispose patients to the development of early onset post-traumatic osteoarthritis. The goal of our study was to examine the longitudinal interrelationship between altered tibial position relative to the femur and cartilage health measured by quantitative T1ρ MRI. Twenty-five patients with isolated unilateral ACL injury underwent kinematic and cartilage T1ρ MRI at baseline prior to ACL reconstruction and then at 1-year post-reconstruction. Tibial position relative to the femur in the anterior-posterior plane was calculated as well as cartilage T1ρ relaxation values in the injured and uninjured knee. At baseline prior to ACL reconstruction, the tibia was in a significantly more anterior position relative to the femur in the ACL deficient knee compared to the healthy contralateral knee. This difference was no longer present at 1-year follow-up. Additionally, the side-side difference in tibial position correlated to increased cartilage T1ρ relaxation values in the medial compartment of the knee 1-year post-reconstruction. Altered tibial position following ACL reconstruction is correlated with detectable cartilage degeneration as soon as 1 year following ACL reconstruction.

Reproducibility measurements of three methods for calculating in vivo MR-based knee kinematics.

PURPOSE: To describe three quantification methods for magnetic resonance imaging (MRI)-based knee kinematic evaluation and to report on the reproducibility of these algorithms. MATERIALS AND METHODS: T2 -weighted, fast-spin echo images were obtained of the bilateral knees in six healthy volunteers. Scans were repeated for each knee after repositioning to evaluate protocol reproducibility. Semiautomatic segmentation defined regions of interest for the tibia and femur. The posterior femoral condyles and diaphyseal axes were defined using the previously defined tibia and femur. All segmentation was performed twice to evaluate segmentation reliability. Anterior tibial translation (ATT) and internal tibial rotation (ITR) were calculated using three methods: a tibial-based registration system, a combined tibiofemoral-based registration method with all manual segmentation, and a combined tibiofemoral-based registration method with automatic definition of condyles and axes. Intraclass correlation coefficients and standard deviations across multiple measures were determined. RESULTS: Reproducibility of segmentation was excellent (ATT = 0.98; ITR = 0.99) for both combined methods. ATT and ITR measurements were also reproducible across multiple scans in the combined registration measurements with manual (ATT = 0.94; ITR = 0.94) or automatic (ATT = 0.95; ITR = 0.94) condyles and axes. CONCLUSION: The combined tibiofemoral registration with automatic definition of the posterior femoral condyle and diaphyseal axes allows for improved knee kinematics quantification with excellent in vivo reproducibility.

Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-ß/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-ß pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1(-/-) mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, [corrected] as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HHT [corrected] in particular and to angiogenesis in general.