Skewed epithelial cell differentiation and premature aging of the thymus in the absence of vitamin D signaling.

Central tolerance of thymocytes to self-antigen depends on the medullary thymic epithelial cell (mTEC) transcription factor autoimmune regulator (Aire), which drives tissue-restricted antigen (TRA) gene expression. Vitamin D signaling regulates Aire and TRA expression in mTECs, providing a basis for links between vitamin D deficiency and autoimmunity. We find that mice lacking Cyp27b1, which cannot produce hormonally active vitamin D, display profoundly reduced thymic cellularity, with a reduced proportion of Aire mTECs, attenuated TRA expression, and poorly defined cortical-medullary boundaries.

Type I interferon induced during chronic viral infection favors B-cell development in the thymus.

Chronic viral infections cause thymic involution yet the potential for broader, longer-term impact on thymic composition remains unexplored. Here we show that chronic, but not acute, lymphocytic choriomeningitis virus infection promotes a unique population of immature B cells in the thymus. We show that chronic viral infection promotes signals within the thymus, including the expression of B-cell activating factor (BAFF), that favor the maturation of this population as these cells acquire expression of CD19 and immunoglobulin M.

Arthroscopy Association of Canada Position Statement on Opioid Prescription After Arthroscopic Surgery.

Background: Despite the ongoing opioid epidemic, most patients are still prescribed a significant number of opioid medications for pain management after arthroscopic surgery. There is a need for consensus among orthopaedic surgeons and solutions to aid providers in analgesic strategies that reduce the use of opioid pain medications.

Purpose: This position statement was developed with a comprehensive systematic review and meta-analysis of exclusively randomized controlled trials (RCTs) to synthesize the best available evidence for managing acute postoperative pain after arthroscopic surgery.

The Effect of Staged Versus Usual Care Physiotherapy on Knee Function Following Anterior Cruciate Ligament Reconstruction.

Context: The long duration and high cost of anterior cruciate ligament reconstruction (ACLR) rehabilitation can pose barriers to completing rehabilitation, the latter stages of which progress to demanding sport-specific exercises critical for a safe return to sport. A staged approach shifting in-person physiotherapy sessions to later months of recovery may ensure patients undergo the sport-specific portion of ACLR rehabilitation. Design/Objective: To compare postoperative outcomes of knee function in patients participating in a staged ACLR physiotherapy program to patients participating in usual care physiotherapy through a randomized controlled trial.

Cutting Edge: Aire Is a Coactivator of the Vitamin D Receptor.

Vitamin D deficiency is associated with the development of autoimmunity, which arises from defects in T cell tolerance to self-antigens. Interactions of developing T cells with medullary thymic epithelial cells, which express tissue-restricted Ags, are essential for the establishment of central tolerance. However, vitamin D signaling in the thymus is poorly characterized.

Low rates of serious complications after open Latarjet procedure at short-term follow-up.

Purpose: To report on intraoperative and short-term postoperative adverse events after open Latarjet procedure in patients with recurrent anterior shoulder instability. These complications were classified into different grades of severity based on the treatment required and the learning curve of the procedure.

Methods: Ninety-six patients (102 shoulders) underwent open Latarjet procedure for recurrent post-traumatic anterior glenohumeral instability between 2012 and 2020.

Active Retrieval Improves Procedural Learning in Orthopedic Surgery.

Objective: Tests are shown to enhance learning: this is known as the "testing effect". The benefit of testing is theorized to be through "active retrieval", which is the effortful process of recalling stored knowledge. This differs from "passive studying", such as reading, which is a low effort process relying on recognition.

The ICOS-ICOSL pathway tunes thymic selection.

Negative selection of developing T cells plays a significant role in T-cell tolerance to self-antigen. This process relies on thymic antigen-presenting cells which express both self-antigens and cosignaling molecules. Inducible T-cell costimulator (ICOS) belongs to the CD28 family of cosignaling molecules and binds to ICOS ligand (ICOSL).

Pre-existing chromatin accessibility and gene expression differences among naive CD4 T cells influence effector potential.

CD4 T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4 T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling.

Arthroscopic Versus Mini-open Rotator Cuff Repair: A Randomized Trial and Meta-analysis.

Background: Patients with complete rotator cuff tears who fail a course of nonoperative therapy can benefit from surgical repair.

Purpose: This randomized trial compared mini-open (MO) versus all-arthroscopic (AA) rotator cuff repair.

Study Design: Randomized controlled trial; Level of evidence, 1.

p16 Regulates Cellular Senescence in PD-1-Expressing Human T Cells.

T-cell dysfunction arising upon repeated antigen exposure prevents effective immunity and immunotherapy. Using various clinically and physiologically relevant systems, we show that a prominent feature of PD-1-expressing exhausted T cells is the development of cellular senescence features both and . This is associated with p16 expression and an impaired cell cycle G1 to S-phase transition in repeatedly stimulated T cells.

NR4A3 Mediates Thymic Negative Selection.

Central tolerance aims to limit the production of T lymphocytes bearing TCR with high affinity for self-peptide presented by MHC molecules. The accumulation of thymocytes with such receptors is limited by negative selection or by diversion into alternative differentiation, including T regulatory cell commitment. A role for the orphan nuclear receptor NR4A3 in negative selection has been suggested, but its function in this process has never been investigated.

Continuous bilateral subomohyoid suprascapular nerve blocks for postoperative analgesia for bilateral rotator cuff repair: a case report.

Purpose: Blocking the suprascapular nerve under the inferior belly of the omohyoid muscle is a novel regional anesthesia technique that has been proposed for shoulder analgesia. We describe the use of and our experience with bilateral indwelling suprascapular catheters for pain management via continuous infusions in a patient undergoing bilateral shoulder surgery.

Clinical Features: Bilateral subomohyoid suprascapular catheters were inserted prior to surgery for postoperative analgesia in a patient undergoing bilateral rotator cuff tear repair.

Strength and Numbers: The Role of Affinity and Avidity in the 'Quality' of T Cell Tolerance.

The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance.

Arthroscopy Association of Canada Position Statement on Exercise for Knee Osteoarthritis: A Systematic Review of Guidelines.

Background: Exercise is widely regarded to improve pain and function in patients with knee osteoarthritis (OA) through building supportive muscle mass, facilitating weight loss, and through the other beneficial effects associated with it.

Purpose: To explore literature that presents clinical guidelines for the use of exercise in the treatment of knee OA to inform an evidence-based position statement for the Arthroscopy Association of Canada.

Study Design: Position statement.

CD5 levels define functionally heterogeneous populations of naïve human CD4 T cells.

Studies in murine models show that subthreshold TCR interactions with self-peptide are required for thymic development and peripheral survival of naïve T cells. Recently, differences in the strength of tonic TCR interactions with self-peptide, as read-out by cell surface levels of CD5, were associated with distinct effector potentials among sorted populations of T cells in mice. However, whether CD5 can also be used to parse functional heterogeneity among human T cells is less clear.

CD5 levels reveal distinct basal T-cell receptor signals in T cells from non-obese diabetic mice.

Type 1 diabetes in non-obese diabetic (NOD) mice occurs when autoreactive T cells eliminate insulin producing pancreatic β cells. While extensively studied in T-cell receptor (TCR) transgenic mice, the contribution of alterations in thymic selection to the polyclonal T-cell pool in NOD mice is not yet resolved. The magnitude of signals downstream of TCR engagement with self-peptide directs the development of a functional T-cell pool, in part by ensuring tolerance to self.

Differential expression of tissue-restricted antigens among mTEC is associated with distinct autoreactive T cell fates.

Medullary thymic epithelial cells (mTEC) contribute to the development of T cell tolerance by expressing and presenting tissue-restricted antigens (TRA), so that developing T cells can assess the self-reactivity of their antigen receptors prior to leaving the thymus. mTEC are a heterogeneous population of cells that differentially express TRA. Whether mTEC subsets induce distinct autoreactive T cell fates remains unclear.

MHC-Independent Thymic Selection of CD4 and CD8 Coreceptor Negative αβ T Cells.

It is becoming increasingly clear that unconventional T cell subsets, such as NKT, γδ T, mucosal-associated invariant T, and CD8αα T cells, each play distinct roles in the immune response. Subsets of these cell types can lack both CD4 and CD8 coreceptor expression. Beyond these known subsets, we identify CD4CD8TCRαβ, double-negative (DN) T cells, in mouse secondary lymphoid organs.

Differential interferon-gamma production potential among naïve CD4 T cells exists prior to antigen encounter.

Individual CD4 T cells can become one of a number of helper (Th) lineages with distinct effector functions. However, whether biases in Th potential exist prior to antigen encounter is unknown. Studies have identified cell-intrinsic functional heterogeneity among naïve T cells that can be parsed based on the strength of T-cell receptor (TCR) interactions with self-peptide.

A randomised trial of observational learning from 2D and 3D models in robotically assisted surgery.

Background: Advances in 3D technology mean that both robotic surgical devices and surgical simulators can now incorporate stereoscopic viewing capabilities. While depth information may benefit robotic surgical performance, it is unclear whether 3D viewing also aids skill acquisition when learning from observing others. As observational learning plays a major role in surgical skills training, this study aimed to evaluate whether 3D viewing provides learning benefits in a robotically assisted surgical task.