Unveiling the Role of the Most Impactful Cardiovascular Risk Locus through Haplotype Editing.

The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease (CAD), accounting for ∼10%-15% of disease in non-African populations. The ∼60 kb risk haplotype is human-specific and lacks coding genes, hindering efforts to decipher its function. Here, we produce induced pluripotent stem cells (iPSCs) from risk and non-risk individuals, delete each haplotype using genome editing, and generate vascular smooth muscle cells (VSMCs). Risk VSMCs exhibit globally altered transcriptional networks that intersect with previously identified CAD risk genes and pathways, concomitant with aberrant adhesion, contraction, and proliferation. Unexpectedly, deleting the risk haplotype rescues VSMC stability, while expressing the 9p21.3-associated long non-coding RNA ANRIL induces risk phenotypes in non-risk VSMCs. This study shows that the risk haplotype selectively predisposes VSMCs to adopt a cell state associated with CAD phenotypes, defines new VSMC-based networks of CAD risk genes, and establishes haplotype-edited iPSCs as powerful tools for functionally annotating the human genome.

Management of Metastatic Disease in Long Bones.

LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.

Evaluation and Management of Intra-Articular Tumors of the Knee.

Intra-articular tumors of the knee are most commonly benign. Overall, this is a relatively rare clinical presentation. The differential diagnosis includes pigmented villonodular synovitis, synovial chondromatosis, lipoma arborescens, synovial hemangioma, and very rarely primary sarcoma (synovial sarcoma being the most common). The clinical presentation for these conditions is usually non-specific, but radiographic and advanced imaging findings are able to differentiate some of these tumors. It is essential to obtain and send tissue specimens to pathology for histologic analysis to rule out a primary malignancy as a missed diagnosis can have grave implications on patient outcomes. This review summarized key aspects of diagnosis and treatment for these conditions.

Management of Primary Aggressive Tumors of the Knee.

Primary bone sarcomas and aggressive benign bone tumors are relatively rare. It is essential to recognize features that are concerning for these aggressive tumors based on a patient's history, physical exam, and radiographs. Physicians and other health care providers should have a high suspicion for these tumors and promptly refer these patients to orthopaedic oncologists. A multidisciplinary, team-based approach is required to obtain an accurate diagnosis and provide comprehensive care. This review discussed the appropriate work-up, biopsy principles, relevant peri-operative medical management, and surgical treatment options for patients with aggressive primary bone tumors around the knee. Primary bone sarcomas (osteosarcoma and chondrosarcoma) and aggressive benign bone tumors (giant cell tumor, chondroblastoma, and chondromyxoid fibroma) that have a predilection to the distal femur and proximal tibia are the focus of this review.

Management of Pathologic Fractures around the Knee: Part 2-Proximal Tibia.

Metastatic disease affecting the proximal tibia is rarer than disease affecting the femur; however, it presents unique challenges that the orthopaedic surgeon must address to ensure successful outcomes and return the patient to an ambulatory status. The essential workup for evaluating and treating these patients is addressed briefly in this review as a summary of the information is provided in part 1 of this series. Part 2 of this series will focus on the surgical treatment of these lesions, which can be complex and is not as well described in the literature. Procedures ranging from open reduction internal fixation with cement augmentation to complex endoprosthetic reconstruction can be employed to address proximal tibia metastatic disease. An awareness of these various treatment modalities allows the orthopaedic surgeon to plan the most effective operation for the patients under their care.

Management of Pathologic Fractures around the Knee: Part 1-Distal Femur.

Pathologic fractures secondary to metastatic disease are an increasingly prevalent problem. Such patients require multidisciplinary collaboration to optimize clinical outcomes. An established algorithm for clinical, laboratory, and radiographic work-up will ensure that each patient achieves the best outcome while avoiding catastrophic complications. Metastatic disease to the region of the knee is less commonly encountered than in other regions of the body, but it presents unique difficulties that merit discussion. Part one of this two-part article series will discuss the appropriate work-up of patients with suspected or impending pathologic fracture of the distal femur, highlight biopsy principles, address perioperative nonsurgical treatments that will optimize patient outcomes, and discuss available surgical treatment modalities.

PRESCILA: a new, lightweight neutron rem meter.

Conventional neutron rem meters currently in use are based on 1960's technology that relies on a large neutron moderator assembly surrounding a thermal detector to achieve a rem-like response function over a limited energy range. Such rem meters present an ergonomic challenge, being heavy and bulky, and have caused injuries during radiation protection surveys. Another defect of traditional rem meters is a poor high-energy response above 10 MeV, which makes them unsuitable for applications at high-energy accelerator facilities. Proton Recoil Scintillator-Los Alamos (PRESCILA) was developed as a low-weight (2 kg) alternative capable of extended energy response, high sensitivity, and moderate gamma rejection. An array of ZnS(Ag) based scintillators is located inside and around a Lucite light guide, which couples the scintillation light to a sideview bialkali photomultiplier tube. The use of both fast and thermal scintillators allows the energy response function to be optimized for a wide range of operational spectra. The light guide and the borated polyethylene frame provide moderation for the thermal scintillator element. The scintillators represent greatly improved versions of the Hornyak and Stedman designs from the 1950's, and were developed in collaboration with Eljen Technology. The inherent pulse height advantage of proton recoils over electron tracks in the phosphor grains eliminates the need for pulse shape discrimination and makes it possible to use the PRESCILA probe with standard pulse height discrimination provided by off-the-shelf health physics counters. PRESCILA prototype probes have been extensively tested at both Los Alamos and the German Bureau of Standards, Physikalisch-Technische Bundesanstalt. Test results are presented for energy response, directional dependence, linearity, sensitivity, and gamma rejection. Initial field tests have been conducted at Los Alamos and these results are also given. It is concluded that PRESCILA offers a viable, ergonomically superior, alternative to traditional rem meters that is effective for a wide range of neutron fields. The probe is capable of excellent sensitivity (40 counts per minute per microSv h-1 for 241AmBe) and extended energy response to beyond 20 MeV. Directional response is uniform (+/-15%) over a wide range of energies. Response linearity has been characterized to over 20 mSv h-1. Gamma rejection is effective in gamma fields up to 2 mSv h-1. The PRESCILA technology has been commercialized and is now offered under license by Ludlum Measurements, Inc.