Ultrasound-guided joint interventions of the lower extremity.

The purpose of this article is to better understand the role ultrasound plays in lower extremity joint interventions. Ultrasound is an important and reliable tool diagnostically and therapeutically. Real-time feedback, lack of ionizing radiation, and dynamic maneuverability make ultrasound an important tool in the proceduralist's armament. This article will touch upon the important anatomic considerations, clinical indications, and technical step-by-step details for lower extremity ultrasound interventions. Specifically, we will look at interventions involving the hip, knee, ankle, and foot. In addition, this article will discuss the roles corticosteroid and platelet-rich plasma may play in certain interventions.

Driver mutation zygosity is a critical factor in predicting clonal hematopoiesis transformation risk.

Clonal hematopoiesis (CH) can be caused by either single gene mutations (eg point mutations in JAK2 causing CHIP) or mosaic chromosomal alterations (e.g., loss of heterozygosity at chromosome 9p). CH is associated with a significantly increased risk of hematologic malignancies. However, the absolute rate of transformation on an annualized basis is low. Improved prognostication of transformation risk is urgently needed for routine clinical practice. We hypothesized that the co-occurrence of CHIP and mCAs at the same locus (e.g., transforming a heterozygous JAK2 CHIP mutation into a homozygous mutation through concomitant loss of heterozygosity at chromosome 9) might have important prognostic implications for malignancy transformation risk. We tested this hypothesis using our discovery cohort, the UK Biobank (n = 451,180), and subsequently validated it in the BioVU cohort (n = 91,335). We find that individuals with a concurrent somatic mutation and mCA were at significantly increased risk of hematologic malignancy (for example, In BioVU cohort incidence of hematologic malignancies is higher in individuals with co-occurring JAK2 V617F and 9p CN-LOH; HR = 54.76, 95% CI = 33.92-88.41, P < 0.001 vs. JAK2 V617F alone; HR = 44.05, 95% CI = 35.06-55.35, P < 0.001). Currently, the 'zygosity' of the CHIP mutation is not routinely reported in clinical assays or considered in prognosticating CHIP transformation risk. Based on these observations, we propose that clinical reports should include 'zygosity' status of CHIP mutations and that future prognostication systems should take mutation 'zygosity' into account.

Cost-Effective and Scalable Clonal Hematopoiesis Assay Provides Insight into Clonal Dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon in which hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP mutations are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or to serial sequencing. In this study, an affordable (approximately US $8 per sample), accurate, and scalable sequencing assay for CHIP is introduced and validated. The efficacy of the assay was demonstrated by identifying CHIP mutations in a cohort of 456 individuals with DNA collected at multiple time points in Vanderbilt University's biobank and quantifying clonal expansion rates over time. A total of 101 individuals with CHIP/clonal cytopenia of undetermined significance were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction at both time points. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. Additionally, mutation co-occurrence and clonal competition between multiple driver mutations were explored.

Lymphoid clonal hematopoiesis: implications for malignancy, immunity, and treatment.

Clonal hematopoiesis (CH) is the age-related expansion of hematopoietic stem cell clones caused by the acquisition of somatic point mutations or mosaic chromosomal alterations (mCAs). Clonal hematopoiesis caused by somatic mutations has primarily been associated with increased risk of myeloid malignancies, while mCAs have been associated with increased risk of lymphoid malignancies. A recent study by Niroula et al. challenged this paradigm by finding a distinct subset of somatic mutations and mCAs that are associated with increased risk of lymphoid malignancy. CH driven by these mutations is termed lymphoid clonal hematopoiesis (L-CH). Unlike myeloid clonal hematopoiesis (M-CH), L-CH has the potential to originate at both stem cells and partially or fully differentiated progeny stages of maturation. In this review, we explore the definition of L-CH in the context of lymphocyte maturation and lymphoid malignancy precursor disorders, the evidence for L-CH in late-onset autoimmunity and immunodeficiency, and the development of therapy-related L-CH following chemotherapy or hematopoietic stem cell transplantation.

Cost-effective and scalable clonal hematopoiesis assay provides insight into clonal dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon that occurs when hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or serial sequencing. Here, we present and validate a CHIP targeted sequencing assay that is affordable (∼$8/sample), accurate and highly scalable. To demonstrate the utility of this assay, we detected CHIP in a cohort of 456 individuals with DNA collected at multiple timepoints in the Vanderbilt BioVU biobank and quantified clonal expansion rates over time. A total of 101 individuals with CHIP were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction (VAF) at both timepoints. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. We further describe the mutation co-occurrence and clonal competition between multiple driver mutations.

Citrullination of fibronectin alters integrin clustering and focal adhesion stability promoting stromal cell invasion.

The extracellular matrix (ECM) microenvironment is increasingly implicated in the instruction of pathologically relevant cell behaviors, from aberrant transdifferentation to invasion and beyond. Indeed, pathologic ECMs possess a panoply of alterations that provide deleterious instructions to resident cells. Here we demonstrate the precise manner in which the ECM protein fibronectin (FN) undergoes the posttranslational modification citrullination in response to peptidyl-arginine deiminase (PAD), an enzyme associated with innate immune cell activity and implicated in systemic ECM-centric diseases, like cancer, fibrosis and rheumatoid arthritis. FN can be citrullinated in at least 24 locations, 5 of which reside in FN's primary cell-binding domain. Citrullination of FN alters integrin clustering and focal adhesion stability with a concomitant enhancement in force-triggered integrin signaling along the FAK-Src and ILK-Parvin pathways within fibroblasts. In vitro migration and in vivo wound healing studies demonstrate the ability of citrullinated FN to support a more migratory/invasive phenotype that enables more rapid wound closure. These findings highlight the potential of ECM, particularly FN, to "record" inflammatory insults via post-translational modification by inflammation-associated enzymes that are subsequently "read" by resident tissue fibroblasts, establishing a direct link between inflammation and tissue homeostasis and pathogenesis through the matrix.