Fractures of the posterior malleolus: a systematic review and analysis of patient-reported outcome scale selection.

PURPOSE: Despite the extensive use of PROs in ankle fracture research, no study has quantified which PROs are most commonly used for assessing outcomes of patients who sustain fractures of the posterior malleolus. The purpose of this study was therefore to quantify which PROs are most commonly used for outcome research after posterior malleolus fractures. METHODS: A systematic search was performed using the preferred reporting items for systematic reviews and meta-analyses guidelines. Articles were identified through Pubmed, EMBASE, Web of Science, and cochrane central register of controlled trials through May of 2021. Included articles were analyzed for the primary outcome of the most commonly reported PRO. RESULTS: The American orthopedic foot and ankle ankle-hindfoot score (AOFAS) was the most commonly used PRO for assessment of posterior malleolus fracture outcomes, used in 37 of 72 studies (51.4%). The second and third most common were the olerud-molander ankle score (OMAS) (22 studies, 30.6%) and the visual analogue score (VAS) (21 studies, 29.2%). Eleven different PROs were used only once. Quality of evidence was graded as low given the percentage of studies that were observational or case series (68 of 72 studies, 94.4%). CONCLUSION: Investigators have used many different PROs to assess outcomes for posterior malleolus fractures, the most common of which are the AOFAS, OMAS, and VAS. Future investigators should attempt to unify outcome reporting for these injuries.

Extensor Tendon Injury After Volar Locking Plating for Distal Radius Fractures: A Systematic Review.

Distal radius fractures are common orthopedic injuries. Treatment has varied historically, but volar locking plating currently predominates. Although flexor tendon injury is a well-studied complication of this operation, extensor tendon injury is less well studied. The purpose of this review is to search the literature and present the epidemiology, presentation, and treatment of this complication. The Cochrane, EMBASE, PubMed, and SCOPUS databases were searched for the terms "volar" + "radius" + ("plate" OR "plating") + "extensor." Ninety final studies were included for analysis in this review. The incidence of extensor tendon rupture varies from 0% to 12.5%; the extensor pollicis longus is most commonly ruptured. The presentation and management of extensor tendon injury after injury, intraoperatively, and postoperatively are summarized. Radiographic views are described to detect screw prominence and minimize intraoperative risk. Extensor tendon injury after volar locking plate for distal radius fractures is an uncommon injury with several risk factors including dorsal screw prominence and fracture fragments. Removal of hardware and tendon transfers or reconstruction may be necessary to prevent loss of extensor mechanism.

Return-to-Competition Criteria After Ulnar Collateral Ligament Reconstruction: A Systematic Review and Meta-analysis.

BACKGROUND: Injury to the ulnar collateral ligament of the elbow is common among overhead throwing athletes and can result in significant functional limitations. While surgical reconstruction offers high rates of return to competition, there are no validated or universally accepted guidelines for determining when an athlete can safely resume play. PURPOSE: To assess the existing scientific literature for return-to-competition criteria utilized after ulnar collateral ligament reconstruction. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: The PubMed database was searched for clinical investigations of ulnar collateral ligament reconstruction in overhead throwing athletes published between January 2000 and June 2020. Only studies that had a minimum follow-up of 1 year and included at least 1 specific return-to-competition criterion were considered. RESULTS: A total of 15 studies were included in the final analysis, encompassing 1156 patients with an average age of 20.7 years (SD, 2.0 years). Baseball players composed 96.3% of patients for whom sport was specified, and 92.4% of baseball players were pitchers. The most common return-to-competition criterion, identified in 87% of studies, was completion of a return-to-throwing program, which started on average 16.7 weeks (range, 12-18 weeks) after surgery. A return-to-mound program was utilized in 53% of studies, starting on average 7.4 months (range, 6-9 months) postoperatively. Minimum time from surgery was used in 73% studies, with players waiting 7 to 12 months (mean, 9.7; SD, 1.4 months) after surgery before return-to-competition consideration. The overall rate of return to competition at the preinjury level or higher was 85.7% (SD, 8.5%) at an average of 12.2 months (SD, 0.6 months). CONCLUSION: In general, we observed a paucity of literature describing the return-to-competition process after ulnar collateral ligament reconstruction in overhead throwing athletes. Only 3 explicit return-to-competition criteria were identified across all studies: completion of a return-to-throwing program, completion of a return-to-mound program for pitchers, and minimum time from surgery. Increased transparency regarding postoperative rehabilitation protocols and further research are necessary to identify and validate sport-specific return-to-competition criteria, which will ultimately help athletes return to play in a safe and timely fashion after ulnar collateral ligament reconstruction.

The history of orthopaedic surgery in India: from antiquity to present.

Indian orthopedists have a legacy dating back more than 4000 years. Starting with the Harappan civilization, ancient orthopaedic surgeons reduced fractures and conducted therapeutic trepanations. Since then, Indian physicians have pioneered many of the orthopaedic techniques still used today - including the use of prosthetics, fracture tables, and rehabilitative physical therapy. Today, orthopaedic surgeons coexist with traditional Indian bonesetters. Although bonesetting practices can have complication rates as high as 40%, bonesetters still handle a majority of fractures in India and are often culturally preferred. Importantly though, bonesetters are often the only expedient option available in both rural and urban settings.

Microvascular Anatomy and Intrinsic Gene Expression of Menisci From Young Adults.

BACKGROUND: Meniscal vascular supply is an important determinant of its healing potential. It has been reported that only the peripheral 30% of the meniscus is vascularized in cadavers aged 53 to 94 years; however, the vascularity in young patients, in whom meniscal repair is more often performed, is unknown. PURPOSE: The primary objective was to analyze and measure the microvascular anatomy of the meniscus in adult cadaveric specimens <35 years old. The secondary objective was to assess angiogenic potential by quantifying regional gene expression in a meniscal allograft cohort <45 years old. STUDY DESIGN: Descriptive laboratory study. METHODS: In part 1 of this study, 13 fresh-frozen cadaveric knees (age range, 22-34 years; mean, 28.5 years) underwent popliteal artery India ink injection and tissue clearing using a Spalteholz technique, followed by microvascular vascular measurement. In part 2, mRNA was isolated from 13 meniscal allografts (age range, 17-43 years; mean, 27.2 years), and expression of angiogenic genes, vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor 1 (FLT1) was quantified using real-time polymerase chain reaction. RESULTS: The maximal depth of vascular penetration into the periphery of the medial and lateral menisci ranged from 0% to 42% and 0% to 48%, respectively. There was variation in the degree of vascular penetration within the medial meniscus, with the posterior horn having a significantly smaller depth of penetration (median, 8.7%) than that of the anterior horn (median, 17.4%; P < .0001) or midbody (median, 17.5%; P = .0003). There were no differences in angiogenesis gene expression (VEGF/FLT1) based on circumferential or radial meniscal locations. CONCLUSION: The vascular supply of the medial and lateral menisci in specimens from adults <35 years of age extended farther than what was reported in specimens from older individuals; however, median values remained consistent. Gene expression of the angiogenic marker VEGF was low throughout all regions of uninjured menisci from young adults, which is consistent with reports in older specimens. CLINICAL RELEVANCE: Improved understanding of meniscal vascular supply in young adults is critical to informing clinical treatment decisions.

Curriculum Reform and New Technology to Fill the Void of Musculoskeletal Education in Medical School Curriculum.

Musculoskeletal (MSK) disease comprises over 20% of all visits to healthcare providers each year, yet a disproportionately small percentage of medical school education focuses on MSK disease. Even among students applying into orthopaedic surgery, less than 50% demonstrate prerequisite anatomic knowledge before beginning their residency. Medical school curriculum reform is needed, given that only 15% have a required MSK curriculum. Inadequate education ultimately leads to poor patient care and forces clinicians to learn MSK medicine later in practice. Although this inadequacy in medical school MSK education has been recognized for decades, little has changed to address this critical deficiency. A successful curriculum development requires defining critical MSK topics, evaluative methods to assess knowledge acquisition, and ultimately assessment of applying that knowledge to the care of patients. Newer strategies for MSK education include "near-peer" learning from senior classmates and residents, clinical immersion within MSK care teams, peer interest groups, and standardize learning platforms and assessment tools. Technologies such as virtual reality simulation, adaptive video learning, and other technologies will inform the development of affordable, succinct, evidence-informed curriculums that can enhance medical student MSK education with universal implementation. As clinical practice evolves to optimize patient care, so should the education of physicians who deliver that care.

The relationship of pelvic incidence to post-operative total hip arthroplasty dislocation in patients with lumbar fusion.

PURPOSE: To determine if lumbar fusion increases the risk of dislocation following total hip arthroplasty (THA) via a posterior approach and to investigate anatomic variables associated with this increased risk. METHODS: Five-year retrospective review of THAs performed through a posterior approach identifying cases of post-operative dislocation. Patients were grouped into those with or without previous lumbar spine fusion. Lumbar fusion patients were then further analyzed in terms of cup position, pelvic incidence, sacral slope, and pelvic tilt to determine if there were specific variables associated with the increased risk of dislocation. RESULTS: Five hundred nine primary THAs in 460 patients (non-simultaneous bilateral THAs in 41 patients) met inclusion criteria with a dislocation rate of 5.5%. Thirty-one patients were identified as having prior lumbar fusions. The dislocation rate was significantly higher in fusion patients (29 vs 4%; p = 0.009) yielding a relative risk (RR) of dislocation of 4.77 (p = < 0.0001). Additionally, cup anteversion was significantly different between groups (26.8 vs 21.42; p = 0.009). Dislocators in the fusion group were also at greater risk of requiring subsequent revision (RR = 3.24; p = 0.003). Subgroup analysis of fusion patients revealed that dislocators had lower pelvic incidence and sacral slope compared to non-dislocators (45.2 vs 58.6 [p = 0.0029] and 26.3 vs 35.6 [p = 0.0384] respectively). CONCLUSIONS: Patients with lumbar fusion are at increased risk for post-operative dislocations requiring revision. Together, lower pelvic incidence and decreased sacral slope are associated with increased risk of dislocation in these patients.

Glioblastoma multiforme-derived extracellular vesicles drive normal astrocytes towards a tumour-enhancing phenotype.

Glioblastoma multiforme (GBM) is a devastating tumour with abysmal prognoses. We desperately need novel approaches to understand GBM biology and therapeutic vulnerabilities. Extracellular vesicles (EVs) are membrane-enclosed nanospheres released locally and systemically by all cells, including tumours, with tremendous potential for intercellular communication. Tumour EVs manipulate their local environments as well as distal targets; EVs may be a mechanism for tumourigenesis in the recurrent GBM setting. We hypothesized that GBM EVs drive molecular changes in normal human astrocytes (NHAs), yielding phenotypically tumour-promoting, or even tumourigenic, entities. We incubated NHAs with GBM EVs and examined the astrocytes for changes in cell migration, cytokine release and tumour cell growth promotion via the conditioned media. We measured alterations in intracellular signalling and transformation capacity (astrocyte growth in soft agar). GBM EV-treated NHAs displayed increased migratory capacity, along with enhanced cytokine production which promoted tumour cell growth. GBM EV-treated NHAs developed tumour-like signalling patterns and exhibited colony formation in soft agar, reminiscent of tumour cells themselves. GBM EVs modify the local environment to benefit the tumour itself, co-opting neighbouring astrocytes to promote tumour growth, and perhaps even driving astrocytes to a tumourigenic phenotype. Such biological activities could have profound impacts in the recurrent GBM setting.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.

HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line.

BACKGROUND: Agents targeting HSP90 and GRP94 are seldom tested in stressed contexts such as heat shock (HS) or the unfolded protein response (UPR). Tumor stress often activates HSPs and the UPR as pro-survival mechanisms. This begs the question of stress effects on chemotherapeutic efficacy, particularly with drugs targeting chaperones such as HSP90 or GRP94. We tested the utility of several HSP90 inhibitors, including PU-H71 (targeting GRP94), on a primary canine lung cancer line under HS/UPR stress compared to control conditions. METHODS: We cultured canine bronchoalveolar adenocarcinoma cells that showed high endogenous HSP90 and GRP94 expression; these levels substantially increased upon HS or UPR induction. We treated cells with HSP90 inhibitors 17-DMAG, 17-AAG or PU-H71 under standard conditions, HS or UPR. Cell viability/survival was assayed. Antibody arrays measured intracellular signalling and apoptosis profiles. RESULTS: HS and UPR had varying effects on cells treated with different HSP90 inhibitors; in particular, HS and UPR promoted resistance to inhibitors in short-term assays, but combinations of UPR stress and PU-H571 showed potent cytotoxic activity in longer-term assays. Array data indicated altered signalling pathways, with apoptotic and pro-survival implications. UPR induction + dual targeting of HSP90 and GRP94 swayed the balance toward apoptosis. CONCLUSION: Cellular stresses, endemic to tumors, or interventionally inducible, can deflect or enhance chemo-efficacy, particularly with chaperone-targeting drugs. Stress is likely not held accountable when testing new pharmacologics or assessing currently-used drugs. A better understanding of stress impacts on drug activities should be critical in improving therapeutic targeting and in discerning mechanisms of drug resistance.

Proteomic analyses of brain tumor cell lines amidst the unfolded protein response.

Brain tumors such as high grade gliomas are among the deadliest forms of human cancers. The tumor environment is subject to a number of cellular stressors such as hypoxia and glucose deprivation. The persistence of the stressors activates the unfolded proteins response (UPR) and results in global alterations in transcriptional and translational activity of the cell. Although the UPR is known to effect tumorigenesis in some epithelial cancers, relatively little is known about the role of the UPR in brain tumors. Here, we evaluated the changes at the molecular level under homeostatic and stress conditions in two glioma cell lines of differing tumor grade. Using mass spectrometry analysis, we identified proteins unique to each condition (unstressed/stressed) and within each cell line (U87MG and UPN933). Comparing the two, we find differences between both the conditions and cell lines indicating a unique profile for each. Finally, we used our proteomic data to identify the predominant pathways within these cells under unstressed and stressed conditions. Numerous predominant pathways are the same in both cell lines, but there are differences in biological and molecular classifications of the identified proteins, including signaling mechanisms, following UPR induction; we see that relatively minimal proteomic alterations can lead to signaling changes that ultimately promote cell survival.

Glioma-derived extracellular vesicles selectively suppress immune responses.

BACKGROUND: Glioma-related immunosuppression is well documented; however, the mechanisms of suppression are not fully understood. Here we explore a role for glioma extracellular vesicles (EVs) as a means of immune modulation. METHODS: Healthy donor peripheral blood mononuclear cells (PBMCs) were incubated with mitogenic stimuli and various concentrations of glioma-derived EVs. Intracellular signaling and cytokine output were determined by protein microarrays, and phenotypic changes were assessed by flow cytometry. Recall antigen testing, mixed lymphocyte reactions, and migration assays analyzed PBMC functional capacity. RESULTS: Protein microarray data revealed induction of an immunosuppressive phenotype and cytokine output at high tumor-vesicle concentrations but an activated phenotype at low concentrations. T cell activation antigen expression confirmed differential activation profiles. Functional analyses revealed decreased migratory capacity of PBMCs after incubation with EVs; however, recall antigen and mixed lymphocyte tests indicated that activation capacity is still retained in EV-treated cells. CONCLUSION: The differential effects of high and low EV concentrations dictate modulatory effects on PBMCs. These data provide a role for EVs at high concentrations for inducing selective tolerance of an immune response in a tumor setting. This suggests that lymphocytes in patients' circulation are not irreparably impaired, as previously thought, but can be rescued to augment antitumor responses.

Exosome proteomics reveals transcriptional regulator proteins with potential to mediate downstream pathways.

Exosomes are virus-sized, membrane-enclosed vesicles with origins in the cellular endosomal system, but are released extracellularly. As a population, these tiny vesicles carry relatively enormous amounts of information in their protein, lipid and nucleic acid content, and the vesicles can have profound impacts on recipient cells. This review employs publically-available data combined with gene ontology applications to propose a novel concept, that exosomes transport transcriptional and translational machinery that may have direct impacts on gene expression in recipient cells. Here, we examine the previously published proteomic contents of medulloblastoma-derived exosomes, focusing on transcriptional regulators; we found that there are numerous proteins that may have potential roles in transcriptional and translational regulation with putative influence on downstream, cancer-related pathways. We expanded this search to all of the proteins in the Vesiclepedia database; using gene ontology approaches, we see that these regulatory factors are implicated in many of the processes involved in cancer initiation and progression. This information suggests that some of the effects of exosomes on recipient cells may be due to the delivery of protein factors that can directly and fundamentally change the transcriptional landscape of the cells. Within a tumor environment, this has potential to tilt the advantage towards the cancer.