An Uncommon Case of Upper-Extremity Mucormycosis in a Patient With Acute Myeloid Leukemia.

Upper-extremity mucormycosis is a rare, life-threatening fungal infection mainly affecting immunocompromised patients. We report a case of a 30-year-old woman with acute myelogenous leukemia who developed this infection during her hospital stay. The culprit was Mucorales, a subgroup of Zygomycetes species known for fast-progressing, highly lethal infections. She presented with fever, chills, and a lesion on her left forearm that worsened despite initial broad-spectrum antibiotics. A punch biopsy confirmed the diagnosis, leading to antifungal therapy with isavuconazonium sulfate and later amphotericin B, combined with surgery. Timely intervention is critical because delayed treatment can result in severe complications and death. Early suspicion, histology, microscopy, and fungal cultures are vital for accurate diagnosis. Treatment primarily involves amphotericin B, whereas adjunctive therapies such as topical amphotericin B and hyperbaric oxygen show promise. This case underscores the importance of prompt medical and surgical action, enhancing early detection of mucormycosis in immunocompromised patients.

Association of Infrapatellar Fat Pad Fibrosis at 3 Months After ACL Reconstruction With Short-term Clinical Outcomes and Inflammatory Cytokine Levels in the Synovial Fluid.

Background: Infrapatellar fat pad (IFP) fibrosis is reportedly associated with anterior knee pain and the progression of patellofemoral osteoarthritis after anterior cruciate ligament reconstruction (ACLR). However, causes of IFP fibrosis after ACLR have not been sufficiently investigated. Purpose: To compare the descriptive characteristics, clinical outcomes, and inflammatory cytokine levels in the synovial fluid between patients who underwent ACLR with versus without severe IFP fibrosis. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who underwent primary ACLR using autologous hamstring tendon were divided into 2 groups based on magnetic resonance imaging IFP fibrosis scoring (grades 0-5) at 3 months after surgery: the severe fibrosis group (grades 4 and 5) and mild fibrosis group (grades 0-3). Synovial fluid was aspirated on postoperative day 3 or 4 to measure inflammatory cytokine levels. Patient characteristics, clinical outcomes at 3 and 12 months after surgery, and inflammatory cytokine (interleukin [IL]-1ß, IL-2, IL-6, IL-8, IL-10, tumor necrosis factor-α, and interferon-γ) levels were compared between the groups. Results: Of the 36 patients included, 7 were allocated to the severe fibrosis group and 29 were allocated to the mild fibrosis group. The severe fibrosis group had a significantly longer operation time (153.0 vs 116.5 minutes for mild fibrosis; P = .007). Compared with the mild fibrosis group, the severe fibrosis group had greater pain during stair climbing (2.0 vs 0.7; P = .01) and a lower extension muscle strength ratio (operated/healthy side, 52.9% vs 76.1%; P < .001) at 3 months, and the severe fibrosis group had a lower Lysholm score (93.7 vs 97.3; P = .026) and greater knee extension (0.3° vs 1.9°; P = .043) and flexion angle restriction (142.9° vs 149.0°; P = .013) at 12 months. The severe fibrosis group demonstrated higher IL-1ß (2.6 vs 1.4 pg/mL; P = .022), IL-6 (2.0 vs 1.1 ng/mL; P = .029), and interferon-γ levels (11.3 vs 4.0 pg/mL; P = .044). Conclusion: Severe IFP fibrosis was associated with a longer operation time, higher inflammatory cytokine level in the synovial fluid, and worse clinical outcomes at 3 and 12 months after ACLR.

Over 90% of Childhood BCG Vaccine-Induced Keloids in Japan Occur in Women.

INTRODUCTION: Keloids are a fibroproliferative, multifactorial, cutaneous disorder whose pathophysiology is not completely understood. Various factors such as high blood pressure, pregnancy, female gender, mechanical tension of local sites, and prolonged wound healing are known to worsen keloids. Childhood-onset keloids are keloids that form before 10 years of age, before various factors in adulthood come into play, and thus studying childhood-onset keloids may provide additional insight into the underlying mechanisms that lead to keloid formation. METHODS: Retrospective chart review was performed on all patients with childhood-onset keloids who were evaluated at our plastic surgery clinic (one of the largest keloid referral centers in Japan) over a 1-year period. RESULTS: Of the 1443 patients with diagnosis of keloids, 131 patients had childhood-onset keloids. Of these, 106 patients (80.9%) were female, 38.9% of patients had family history of keloids, and 48.9% of patients had allergies or allergy-related conditions (asthma, atopic dermatitis, or allergic rhinitis). Vaccination (47.5%) and chickenpox (19.9%) were the most common triggers. Of vaccinations, BCG was the most common trigger. The majority of keloids from BCG were in female patients (92.9%). The most common location was the chest in male patients (30.0%) and the arm in female patients (41.1%). CONCLUSION: To our knowledge, this is the largest report in the literature on childhood-onset keloids. There was overall female predominance in childhood-onset keloids, and even more significant female predominance in BCG-induced keloids.

Discrepancy between Radiographic and Arthroscopic Findings of Thumb Basilar Joint Arthritis: A Preliminary Clinical Report.

The radiographic staging of arthritic changes in the thumb carpometacarpal (CMC) joint is known to have poor correlation with pain level. This may be due to the limited ability of radiographs to evaluate degenerative changes. The purpose of this study was to examine the relationship between radiographic versus arthroscopic findings of thumb CMC and scaphotrapeziotrapezoidal (STT) joint arthritis. Methods: Twenty patients with symptomatic thumb CMC arthritis underwent arthroscopy of thumb CMC and STT joints with concomitant synovectomy or arthroplasty depending on the degree of articular degeneration found. All patients had preoperative radiographs of the thumb CMC and STT joints. Radiographic degeneration was graded based on the Eaton-Glickel classification. Intraoperative arthroscopic images were reviewed and graded based on the Brown grading system. Results: At the thumb CMC joint, five patients had discordant radiographic and arthroscopic findings of arthritis. At the STT joint, one patient had discordant radiographic and arthroscopic findings of arthritis. Conclusions: In comparing the two staging systems, we found a small subset of patients that demonstrated significant discrepancies. Clinical evaluation remains essential, and patients should be informed that radiographs may underestimate the actual severity of arthritis.

Do Proposed Quality Measures for Carpal Tunnel Release Reveal Important Quality Gaps and Are They Reliable?

BACKGROUND: The American Academy of Orthopaedic Surgeons recently proposed quality measures for the initial surgical treatment of carpal tunnel syndrome (CTS). One measure addressed avoidance of adjunctive surgical procedures during carpal tunnel release; and a second measure addressed avoidance of routine use of clinic-based occupational and/or physical therapy (OT/PT) after carpal tunnel release. However, for quality measures to serve their intended purposes, they must be tested in real-world data to establish that gaps in quality exist and that the measures yield reliable performance information. QUESTIONS/PURPOSES: (1) Is there an important quality gap in clinical practice for avoidance of adjunctive surgical procedures during carpal tunnel release? (2) Is there an important quality gap in avoiding routine use of clinic-based occupational and/or physical therapy after carpal tunnel release? (3) Do these two quality measures have adequate beta-binomial signal-to-noise ratio (SNR) and split-sample reliability (SSR)? METHODS: This retrospective comparative study used a large national private insurance claims database, the 2018 Optum Clinformatics® Data Mart. Ideally, healthcare quality measures are tested within data reflective of the providers and payors to which the measures will be applied. We previously tested these measures in a large public healthcare system and a single academic medical center. In this study, we sought to test the measures in the broader context of patients and providers using private insurance. For both measures, we included the first carpal tunnel release from 28,083 patients performed by one of 7236 surgeons, irrespective of surgical specialty (including, orthopaedic, plastic, neuro-, and general surgery). To calculate surgeon-level descriptive and reliability statistics, analyses were focused on the 66% (18,622 of 28,083) of patients who received their procedure from one of the 24% (1740 of 7236) of surgeons with at least five carpal tunnel releases in the database. No other inclusion/exclusion criteria were applied. To determine whether the measures reveal important gaps in treatment quality (avoidance of adjunctive procedures and routine therapy), we calculated descriptive statistics (median and interquartile range) of the performance distribution stratified by surgeon-level annual volume of carpal tunnel releases in the database (5+, 10+, 15+, 20+, 25+, and 30+). Like the Centers for Medicare & Medicaid Services (CMS), we considered a measure "topped out" if median performance was greater than 95%, meaning the opportunity for further quality improvement is low. We calculated the surgeon-level beta-binomial SNR and SSR for each measure, each stratified by the number of carpal tunnel releases performed by each surgeon in the database. These are standard measures of reliability in health care quality measurement science. The SNR quantifies the proportion of variance that is between rather than within surgeons, and the SSR is the correlation of performance scores when each surgeons' patients are split into two random samples and then corrected for sample size. RESULTS: We found that 2% (308 of 18,622) of carpal tunnel releases involved an adjunctive procedure. The results showed that avoidance of adjunctive surgical procedures during carpal tunnel release had a median (IQR) performance of 100% (100% to 100%) at all case volumes. Only 8% (144 of 1740) of surgeons with at least five cases in the database had less than 100% performance, and only 5% (84 of 1740) had less than 90% performance. This means adjunctive procedures were rarely performed and an important quality gap does not exist based on the CMS criterion. Regarding the avoidance of routine therapy, there was a larger quality gap: For surgeons with at least five cases in the database, median performance was 89% (75% to 100%), and 25% (435 of 1740) of these surgeons had less than 75% performance. This signifies that the measure is not topped out and may reveal an important quality gap. Most patients receiving clinic-based OT/PT had only one visit in the 6 weeks after surgery. Median (IQR) SNRs of the first measure, which addressed avoidance of adjunctive surgical procedures, and the second measure, which addresses avoidance of routine use clinic-based OT/PT, were 1.00 (1.00 to 1.00) and 0.86 (0.67 to 1.00), respectively. The SSR for these measures were 0.87 (95% CI 0.85 to 0.88) and 0.75 (95% CI 0.73 to 0.77), respectively. All of these reliability statistics exceed National Quality Forum's emerging minimum standard of 0.60. CONCLUSION: The first measure, the avoidance of adjunctive surgical procedures during carpal tunnel release, lacked an important quality gap suggesting it is unlikely to be useful in driving improvements. The second measure, avoidance of routine use of clinic-based OT/PT, revealed a larger quality gap and had very good reliability, suggesting it may be useful for quality monitoring and improvement purposes. CLINICAL RELEVANCE: As healthcare systems and payors use the second measure, avoidance of routine use of clinic-based OT/PT, to encourage adherence to clinical practice guidelines (such as provider profiling, public reporting, and payment policies), it will be critically important to consider what proportion of patients receiving OT/PT should be considered routine practice and therefore inconsistent with guidelines. The value or potential harm of this measure depends on this judgement.

"Idiopathic" Shoulder Pain and Dysfunction from Carpal Tunnel Syndrome and Cubital Tunnel Syndrome.

As a referral center for chronic pain, we see many patients with "idiopathic" shoulder pain and limited range of motion. The combination of mild or subclinical carpal tunnel syndrome and cubital tunnel syndrome may be an underrecognized etiology of symptoms in such patients. Here, we report our treatment algorithm and results for such patients. METHODS: Of patients with a chief complaint of shoulder pain, we identified 56 consecutive patients who had pain or tingling with median nerve compression at the proximal wrist crease and positive Tinel's around the cubital tunnel. They were first provided a night-time wrist orthosis. If still symptomatic, nerve blocks were given to median and ulnar nerves under ultrasound guidance. If symptoms recurred after nerve blocks, nerve conduction studies and surgical release of affected nerves were performed. RESULTS: Six patients had 60% or more pain relief with orthosis (mean 4.7 ± 0.8 (SD) to 2.2 ± 0.8). Twenty-three patients had nerve blocks and had persistent pain relief (6.0 ± 1.7 to 2.1 ± 1.9) and significant shoulder motion improvement. Twenty-seven patients only had temporal relief and required surgery but postoperatively had persistent pain relief (6.2 ± 2.0 to 1.2 ± 1.0) and improved shoulder motion. qDASH improved from 33.4 ± 20.1 preoperatively to 12.2 ± 7.4 postoperatively. CONCLUSIONS: All patients had substantial improvement in shoulder pain and motion with compressive neuropathy treatments. Targeted physical examination can identify these patients, who can have significant improvement with appropriate diagnosis and treatment. The study sheds light on an underrecognized cause of shoulder dysfunction.

Inhibition of dengue virus infection by 1-stearoyl-2-arachidonoyl-phosphatidylinositol in vitro.

Dengue fever is an acute febrile infectious disease caused by dengue virus (DENV). Despite the significant public health concerns posed by DENV, there are currently no effective anti-DENV therapeutic agents. To develop such drugs, a better understanding of the detailed mechanisms of DENV infection is needed. Both lipid metabolism and lipid synthesis are activated in DENV-infected cells, so we used lipid screening to identify potential antiviral lipid molecules. We identified 1-stearoyl-2-arachidonoyl-phosphatidylinositol (SAPI), which is the most abundant endogenous phosphatidylinositol (PI) molecular species, as an anti-DENV lipid molecule. SAPI suppressed the cytopathic effects induced by DENV2 infection as well as the replication of all DENV serotypes without inhibiting the entry of DENV2 into host cells. However, no other PI molecular species or PI metabolites, including lysophosphatidylinositols and phosphoinositides, displayed anti-DENV2 activity. Furthermore, SAPI suppressed the production of DENV2 infection-induced cytokines and chemokines, including C-C motif chemokine ligand (CCL)5, CCL20, C-X-C chemokine ligand 8, IL-6, and IFN-ß. SAPI also suppressed the TNF-α production induced by LPS stimulation in macrophage cells differentiated from THP-1 cells. Our results demonstrated that SAPI is an endogenous inhibitor of DENV and modulated inflammatory responses in DENV2-infected cells, at least in part via TLR 4.-Sanaki, T., Wakabayashi, M., Yoshioka, T., Yoshida, R., Shishido, T., Hall, W. W., Sawa, H., Sato, A. Inhibition of dengue virus infection by 1-stearoyl-2-arachidonoyl-phosphatidylinositol in vitro.

Regeneration of Articular Cartilage by Human ESC-Derived Mesenchymal Progenitors Treated Sequentially with BMP-2 and Wnt5a.

The success of cell-based therapies to restore joint cartilage requires an optimal source of reparative progenitor cells and tight control of their differentiation into a permanent cartilage phenotype. Bone morphogenetic protein 2 (BMP-2) has been extensively shown to promote mesenchymal cell differentiation into chondrocytes in vitro and in vivo. Conversely, developmental studies have demonstrated decreased chondrocyte maturation by Wingless-Type MMTV Integration Site Family, Member 5A (Wnt5a). Thus, we hypothesized that treatment of human embryonic stem cell (hESC)-derived chondroprogenitors with BMP-2 followed by Wnt5a may control the maturational progression of these cells into a hyaline-like chondrocyte phenotype. We examined the effects of sustained exposure of hESC-derived mesenchymal-like progenitors to recombinant Wnt5a or BMP-2 in vitro. Our data indicate that BMP-2 promoted a strong chondrogenic response leading to terminal maturation, whereas recombinant Wnt5a induced a mild chondrogenic response without promoting hypertrophy. Moreover, Wnt5a suppressed BMP-2-mediated chondrocyte maturation, preventing the formation of fibrocartilaginous tissue in high-density cultures treated sequentially with BMP-2 and Wnt5a. Implantation of scaffoldless pellets of hESC-derived chondroprogenitors pretreated with BMP-2 followed by Wnt5a into rat chondral defects induced an articular-like phenotype in vivo. Together, the data establish a novel role for Wnt5a in controlling the progression from multipotency into an articular-like cartilage phenotype in vitro and in vivo. Stem Cells Translational Medicine 2017;6:40-50.

A Review of Databases Used in Orthopaedic Surgery Research and an Analysis of Database Use in Arthroscopy: The Journal of Arthroscopic and Related Surgery.

PURPOSE: The purpose of this study was to evaluate how database use has changed over time in Arthroscopy: The Journal of Arthroscopic and Related Surgery and to inform readers about available databases used in orthopaedic literature. METHODS: An extensive literature search was conducted to identify databases used in Arthroscopy and other orthopaedic literature. All articles published in Arthroscopy between January 1, 2006, and December 31, 2015, were reviewed. A database was defined as a national, widely available set of individual patient encounters, applicable to multiple patient populations, used in orthopaedic research in a peer-reviewed journal, not restricted by encounter setting or visit duration, and with information available in English. RESULTS: Databases used in Arthroscopy included PearlDiver, the American College of Surgeons National Surgical Quality Improvement Program, the Danish Common Orthopaedic Database, the Swedish National Knee Ligament Register, the Hospital Episodes Statistics database, and the National Inpatient Sample. Database use increased significantly from 4 articles in 2013 to 11 articles in 2015 (P = .012), with no database use between January 1, 2006, and December 31, 2012. CONCLUSIONS: Database use increased significantly between January 1, 2006, and December 31, 2015, in Arthroscopy. LEVEL OF EVIDENCE: Level IV, systematic review of Level II through IV studies.

Murine supraspinatus tendon injury model to identify the cellular origins of rotator cuff healing.

Purpose of this study: To elucidate the origin of cell populations that contribute to rotator cuff healing, we developed a mouse surgical model where a full-thickness, central detachment is created in the supraspinatus. MATERIALS AND METHODS: Three different inducible Cre transgenic mice with Ai9-tdTomato reporter expression (PRG4-9, αSMA-9, and AGC-9) were used to label different cell populations in the shoulder. The defect was created surgically in the supraspinatus. The mice were injected with tamoxifen at surgery to label the cells and sacrificed at 1, 2, and 5 weeks postoperatively. Frozen sections were fluorescently imaged then stained with Toluidine Blue and re-imaged. RESULTS: Three notable changes were apparent postoperatively. (1) A long thin layer of tissue formed on the bursal side overlying the supraspinatus tendon. (2) The tendon proximal to the defect initially became hypercellular and disorganized. (3) The distal stump at the insertion underwent minimal remodeling. In the uninjured shoulder, tdTomato expression was seen in the tendon midsubstance and paratenon cell on the bursal side in PRG4-9, in paratenon, blood vessels, and periosteum of acromion in SMA-9, and in articular cartilage, unmineralized fibrocartilage of supraspinatus enthesis, and acromioclavicular joint in AGC-9 mice. In the injured PRG4-9 and SMA-9 mice, the healing tissues contained an abundant number of tdTomato+ cells, while minimal contribution of tdTomato+ cells was seen in AGC-9 mice. CONCLUSIONS: The study supports the importance of the bursal side of the tendon to rotator cuff healing and PRG4 and αSMA may be markers for these progenitor cells.

Efficacy of repeated intravenous administration of peramivir against highly pathogenic avian influenza A (H5N1) virus in cynomolgus macaques.

Highly pathogenic avian influenza A (H5N1) viruses cause severe and often fatal disease in humans. We evaluated the efficacy of repeated intravenous dosing of the neuraminidase inhibitor peramivir against highly pathogenic avian influenza virus A/Vietnam/UT3040/2004 (H5N1) infection in cynomolgus macaques. Repeated dosing of peramivir (30 mg/kg/day once a day for 5 days) starting immediately after infection significantly reduced viral titers in the upper respiratory tract, body weight loss, and cytokine production and resulted in a significant body temperature reduction in infected macaques compared with that of macaques administered a vehicle (P < 0.05). Repeated administration of peramivir starting at 24 h after infection also resulted in a reduction in viral titers and a reduction in the period of virus detection in the upper respiratory tract, although the body temperature change was not statistically significant. The macaque model used in the present study demonstrated that inhibition of viral replication at an early time point after infection by repeated intravenous treatment with peramivir is critical for reduction of the production of cytokines, i.e., interleukin-6 (IL-6), tumor necrosis factor α, gamma interferon, monocyte chemotactic protein 1, and IL-12p40, resulting in amelioration of symptoms caused by highly pathogenic avian influenza virus infection.

Peripheral blood mononuclear cells enhance the anabolic effects of platelet-rich plasma on anterior cruciate ligament fibroblasts.

Use of platelet-rich plasma (PRP) has shown promise in various orthopaedic applications, including treatment of anterior cruciate ligament (ACL) injuries. However, various components of blood, including peripheral blood mononuclear cells (PBMCs), are removed in the process of making PRP. It is yet unknown whether these PBMCs have a positive or negative effect on fibroblast behavior. To begin to define the effect of PBMCs on ACL fibroblasts, ACL fibroblasts were cultured on three-dimensional collagen scaffolds for 14 days with and without PBMCs. ACL fibroblasts exposed to PBMCs showed increased type I and type III procollagen gene expression, collagen protein expression, and cell proliferation when the cells were cultured in the presence of platelets and plasma. However, addition of PBMCs to cells cultured without platelets had no effect. The increase in collagen gene and protein expression was accompanied by an increase in IL-6 expression by the PBMCs with exposure to the platelets. Our results suggest that the interaction between platelets and PBMCs leads to an IL-6 mediated increase in collagen expression by ACL fibroblasts.

Arthritis and pneumonitis produced by the same T cell clones from mice with spontaneous autoimmune arthritis.

SKG mice, a newly established model of rheumatoid arthritis (RA), spontaneously develop autoimmune arthritis accompanying extra-articular manifestations, such as interstitial pneumonitis. To examine possible roles of T cells for mediating this systemic autoimmunity, we generated T cell clones from arthritic joints of SKG mice. Two distinct CD8(+) clones were established and both showed in vitro autoreactivity by killing syngeneic synovial cells and a variety of MHC-matched cell lines. Transfer of each clone to histocompatible athymic nude mice elicited joint swelling and histologically evident synovitis accompanying the destruction of adjacent cartilage and bone. Notably, the transfer also produced diffuse severe interstitial pneumonitis. Clone-specific TCR gene messages in the inflamed joints and lungs of the recipients gradually diminished, becoming hardly detectable in 6-11 months; yet, arthritis and pneumonitis continued to progress. Thus, the same CD8(+) T cell clones from arthritic lesions of SKG mice can elicit both synovitis and pneumonitis, which chronically progress and apparently become less T cell dependent in a later phase. The results provide clues to our understanding of how self-reactive T cells cause both articular and extra-articular lesions in RA as a systemic autoimmune disease.