Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses.

Viral hemorrhagic fevers caused by members of the order Bunyavirales comprise endemic and emerging human infections that are significant public health concerns. Despite the disease severity, there are few therapeutic options available, and therefore effective antiviral drugs are urgently needed to reduce disease burdens. Bunyaviruses, like influenza viruses (IFVs), possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We screened compounds from our CEN inhibitor (CENi) library and identified specific structural compounds that are 100 to 1,000 times more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. To investigate their inhibitory mechanism of action, drug-resistant viruses were selected in culture. Whole-genome sequencing revealed that amino acid substitutions in the CEN region of drug-resistant viruses were located in similar positions as those of the CEN α3-helix loop of IFVs derived under drug selection. Thus, our studies suggest that CENi compounds inhibit both bunyavirus and IFV replication in a mechanistically similar manner. Structural analysis revealed that the side chain of the carboxyl group at the seventh position of the main structure of the compound was essential for the high antiviral activity against bunyaviruses. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. These data suggest a potential broad-spectrum clinical utility of CENis for the treatment of both severe influenza and hemorrhagic diseases caused by bunyaviruses.

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.

Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection.

BACKGROUND: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. OBJECTIVES: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. METHODS: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. RESULTS: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. CONCLUSIONS: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

Metacarpal shaft fixation: a biomechanical comparison of dorsal plating, lag screws, and headless compression screws.

BACKGROUND: Metacarpal shaft fractures are common and can be treated nonoperatively. Shortening, angulation, and rotational deformity are indications for surgical treatment. Various forms of treatment with advantages and disadvantages have been documented. The purpose of the study was to determine the stability of fracture fixation with intramedullary headless compression screws in two types of metacarpal shaft fractures and compare them to other common forms of rigid fixation: dorsal plating and lag screw fixation. It was hypothesized that headless compression screws would demonstrate a biomechanical stronger construct. METHODS: Five matched paired hands (age 60.9 ± 4.6 years), utilizing non-thumb metacarpals, were used for comparative fixation in two fracture types created by an osteotomy. In transverse diaphyseal fractures, fixation by headless compression screws (n = 7) and plating (n = 8) were compared. In long oblique diaphyseal fractures, headless compression screws (n = 8) were compared with plating (n = 8) and lag screws (n = 7). Testing was performed using an MTS frame producing an apex dorsal, three point bending force. Peak load to failure and stiffness were calculated from the load-displacement curve generated. RESULTS: For transverse fractures, headless compression screws had a significantly higher stiffness and peak load to failure, means 249.4 N/mm and 584.8 N, than plates, means 129.02 N/mm and 303.9 N (both p < 0.001). For long oblique fractures, stiffness and peak load to failure for headless compression screws were means 209 N/mm and 758.4 N, for plates 258.7 N/mm and 518.5 N, and for lag screws 172.18 N/mm and 234.11 N. There was significance in peak load to failure for headless compression screws vs plates (p = 0.023), headless compression screws vs lag screws (p < 0.001), and plates vs lag screws (p = 0.009). There was no significant difference in stiffness between groups. CONCLUSION: Intramedullary fixation of diaphyseal metacarpal fractures with a headless compression screw provides excellent biomechanical stability. Coupled with lower risks for adverse effects, headless compression screws may be a preferable option for those requiring rapid return to sport or work. LEVEL OF EVIDENCE: Basic Science Study, Biomechanics.

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.

Dihydrodibenzothiepine: Promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor.

This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitor with a carbamoyl pyridone bicycle (CAB) scaffold. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indices, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine is the most promising pharmacophore. The compound (S)-13i showed potent virus titer reduction over oseltamivir phosphate in an in vivo mouse model. The CAB compound described herein served as the lead compound of baloxavir marboxil with a tricyclic scaffold, which was approved in Japan and the USA in 2018.

Articular cartilage protection in Ctsk-/- mice is associated with cellular and molecular changes in subchondral bone and cartilage matrix.

Osteoarthritis (OA) is a degenerative disease and a major cause of chronic disability in aging individuals. Cathepsin K (CatK), encoded by the Ctsk gene, has been implicated in the pathogenesis of pycnodysostosis and osteoporosis. The use of a selective inhibitor of CatK was recently shown to delay OA progression in rabbits. However, the cellular mechanisms underlying these protective effects remain unexplored. We examined articular cartilage maintenance and joint bone remodeling using Ctsk null mice (Ctsk-/- ) which underwent destabilization of the medial meniscus (DMM). We found that Ctsk-/- mice displayed delayed remodeling of subchondral and calcified cartilage by osteoclasts and chodroclasts respectively in DMM-induced osteoarthritis. While WT mice displayed a more severe OA phenotype than Ctsk-/- mice at 16 weeks, higher subchondral bone volume and lower trabecular spacing were also observed in surgically-induced OA joints of Ctsk-/- mice. However, no differences were seen in non-surgical controls. During OA progression, TRAP+ osteoclast numbers were increased in both WT and Ctsk-/- mice. However, Ctsk-/- mice had fewer physis-derived chondroclasts than WT when OA was present. These data suggest that CatK may differentially regulate chondroclastogenesis in the growth plate. Targeted PCR arrays of RNA harvested from laser captured osteoclasts in the subchondral bone and chondroclasts in the growth plate demonstrated differential expression of Atp6v0d2, Tnfrsf11a, Ca2, Calcr, Ccr1, Gpr68, Itgb3, Nfatc1, and Syk genes between WT and Ctsk-/- mice at 8- and 16-weeks post-DMM. Our data provide insight into the cellular mechanisms by which cathepsin K deletion delays OA progression in mice.

Biomechanical Comparison of Fifth Carpometacarpal Fusion Methods: Kirschner Wires Versus Plate and Screws.

BACKGROUND: Fractures and dislocations of the base of the fifth metacarpal can lead to arthritis of the fifth carpometacarpal (CMC) joint. For patients who are symptomatic and fail conservative management, arthrodesis of the fifth CMC joint can be offered. The fusion can be performed using Kirschner wires (K-wires), but can lead to complications such as pin tract infection and pin migration. A low-profile locking plate may represent an attractive alternative. The purpose of this study was to compare the biomechanical stability of these 2 fusion techniques. METHODS: Twelve fresh frozen cadaver hands were divided into 2 groups. The first group underwent fixation of the fifth CMC joint using 2 1.6 mm (0.062 inches) diameter K-wires in a cross-pin configuration. The second group underwent fixation using a 2.0 mm locking plate with 2 locking screws in the hamate and 3 nonlocking screws in the fifth metacarpal shaft. The specimens were then loaded in extension until failure. RESULTS: The stiffness was 15.0±7.2 N/mm for the K-wire group and 14.7±6.0 N/mm (mean±SD) for the plate group (P=0.9366). The peak loads were 62.5±40.0 N and 64.6±24.8 N for K-wire and plate groups, respectively (P=0.9181). The energy to peak load was 294±281 N mm for the K-wire group and 418±190 N mm for the plate group (P=0.3904). CONCLUSIONS: Fifth CMC fusion using either K-wires or plate and screws showed no significant difference in stiffness, peak load, and energy to peak load. These results suggest the 2 methods provide similar biomechanical stability.

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.

Identification of a progenitor cell population destined to form fracture fibrocartilage callus in Dickkopf-related protein 3-green fluorescent protein reporter mice.

Fracture healing is a complex biological process involving the proliferation of mesenchymal progenitor cells, and chondrogenic, osteogenic, and angiogenic differentiation. The mechanisms underlying the proliferation and differentiation of mesenchymal progenitor cells remain unclear. Here, we demonstrate Dickkopf-related protein 3 (Dkk3) expression in periosteal cells using Dkk3-green fluorescent protein reporter mice. We found that proliferation of mesenchymal progenitor cells began in the periosteum, involving Dkk3-positive cell proliferation near the fracture site. In addition, Dkk3 was expressed in fibrocartilage cells together with smooth muscle α-actin and Col3.6 in the early phase of fracture healing as a cell marker of fibrocartilage cells. Dkk3 was not expressed in mature chondrogenic cells or osteogenic cells. Transient expression of Dkk3 disappeared in the late phase of fracture healing, except in the superficial periosteal area of fracture callus. The Dkk3 expression pattern differed in newly formed type IV collagen positive blood vessels and the related avascular tissue. This is the first report that shows Dkk3 expression in the periosteum at a resting state and in fibrocartilage cells during the fracture healing process, which was associated with smooth muscle α-actin and Col3.6 expression in mesenchymal progenitor cells. These fluorescent mesenchymal lineage cells may be useful for future studies to better understand fracture healing.

Discovery of novel 5-hydroxy-4-pyridone-3-carboxy acids as potent inhibitors of influenza Cap-dependent endonuclease.

We report the discovery of a novel series of influenza Cap-dependent EndoNuclease (CEN) inhibitors based on the 4-pyridone-carboxylic acid (PYXA) scaffold, which were found from our chelate library. Our SAR research revealed the lipophilic domain to be the key to CEN inhibition. In particular, the position between the chelate and the lipophilic domain in the derivatives was essential for enhancing the potency. Our study, based on virtual modeling, led to the identification of 2y as a potent CEN inhibitor with an IC50 of 5.12nM.

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.

Distal Scaphoid Excision and Dermal Allograft Interposition in a Professional Athlete: Long-term Follow-up.

Scaphoid nonunion occurs in 10%-15% of scaphoid fractures, potentially resulting in scaphoid nonunion advanced collapse. Distal scaphoid excision without allograft interposition is a known treatment, but can result in loss of carpal height and pain. This report describes the application of human acellular dermal matrix as an interposition graft after distal scaphoid excision for stage I scaphoid nonunion advanced collapse. Postoperatively, the patient initiated early range of motion and returned to full activity at 6 weeks. He demonstrated resolution of his pain 6 years later.

Low Back Pain Caused by Traction Peripheral Neuropathy Due to Chronic Ankle Instability: Three Clinical Cases.

Non-specific low back pain without identifiable causes on imaging is a common and frustrating problem for both patients and physicians. While proximal symptoms such as shoulder pain from distal upper extremity neuropathies such as carpal tunnel syndrome are well-known, peripheral neuropathy of the foot or ankle is rarely considered in the differential diagnosis for low back pain. This study aims to highlight the potential link between chronic ankle instability (CAI) and low back pain. We present three cases: a 32-year-old woman with chronic low back pain for over 10 years, a 59-year-old woman with transient low back pain after long drives, and a 42-year-old woman with acute low back pain while gardening. All patients had normal imaging studies but exhibited CAI on examination. Diagnostic modalities included the ankle anterior drawer test, application of ankle brace, superficial peroneal nerve (SPN) blocks, and assessment of the active straight leg raise (aSLR) angle. In the first case, low back pain disappeared after SPN neurolysis and ankle ligament reconstruction. The second case showed significant improvement in aSLR and pain reduction with SPN block and ankle brace. The third case experienced substantial pain relief with the use of an ankle brace. These findings suggest that addressing ankle instability and associated traction neuropathy can significantly alleviate low back pain symptoms. CAI may be an underrecognized cause of non-specific low back pain. Interventions such as ankle brace, SPN blocks, SPN decompression, and ankle ligament reconstruction can be effective for diagnosis and treatment, potentially offering relief for patients with chronic low back pain.

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.

Outcomes of Patients Receiving Proximal Row Carpectomy and Meniscus Interposition Allografts for the Treatment of End-Stage Wrist Arthritis: A Comparative Study.

BACKGROUND: Proximal row carpectomy (PRC) is a mainstay of wrist arthritis treatment; however, it is traditionally contraindicated in patients with an affected capitate. The use of soft tissue interposition grafts to resurface the radiocapitate articulation has been previously described to allow for PRC in these patients. In the current study, we reviewed our outcomes using knee meniscus allograft interposition to resurface the radiocapitate articulation in patients who would have otherwise been contraindicated for PRC. METHODS: A retrospective study of patients who underwent PRC with or without meniscus interposition arthroplasty was performed from 2011 to 2022. Patient demographics (age, sex, occupation, hand dominance, etc) were collected. Improvement in pain was the primary outcome. Wrist range of motion and reconstructive failure requiring fusion were the secondary outcomes. RESULTS: We identified a total of 83 patients and 43 met the inclusion criteria. Fifteen patients (35%) underwent PRC with meniscus interposition arthroplasty, and 28 patients (65%) underwent PRC alone. Patients with and without meniscus interposition arthroplasty had documented improvement in pain postoperatively (93% vs 95%, P > .05) at a median follow-up time of 11 (range, 3-38 months) and 9 months (range, 3-64 months), respectively. Postoperative wrist range of motion (flexion: +9 vs -4, P > .05, extension: +12 vs -4, P = .10) trended toward increase in patients undergoing meniscus interposition arthroplasty compared with PRC alone. CONCLUSIONS: Our short- to mid-term outcomes in patients with end-stage wrist arthritis affecting the capitate who undergo PRC and meniscus interposition arthroplasty are comparable with those receiving PRC alone.

Orthopaedic Surgery and Indusry: What our Potential Patients Believe.

PURPOSE: Physician and surgeon involvement in industry has received considerable attention in recent decades. In this study, we outline the perspective of the general US population regarding (1) disclosure, (2) ownership, and (3) compensation between physicians/surgeons and industry. We hypothesize that the general population would be largely supportive of the physician/surgeon-industry relationship. METHODS: An online, survey-based, descriptive study was conducted through a crowdsourcing platform, Amazon Mechanical Turk. Survey respondents were presented with a seven-item questionnaire inquiring about the physician/surgeon and industry relationship. An "attention check" question was included; those who failed this question were excluded. Descriptive statistics were used to assess the data and a McNemar chi-squared test for paired, dichotomous data. RESULTS: A total of 993 respondents were included. Survey responses are summarized in Table 1. 70.6% of respondents stated that it was "important" or "extremely important" to disclose that the patient be informed whether implants used in surgery had been developed by the operating surgeon. 71.1% of respondents reported that it was "important" or "extremely important" to disclose partial ownership within industry. Seventy-one percent of respondents stated it was "important" or "extremely important" to disclose royalty payments pertaining to surgical implants. 95.6% of respondents suggested that it was acceptable for surgeons to accept free airfare and lodging, and 95.2% of respondents stated that it was acceptable for the surgeon to be compensated for time away from practice to learn about new equipment. DISCUSSION: In our survey of 993 respondents, we found that relationships with industry are considered acceptable if appropriate disclosure is given to patients. We also found that although respondents suggested that physicians and surgeons may be influenced by a free meal, compensation for trips to try new equipment and time spent away from practice is considered appropriate. LEVEL OF EVIDENCE: 2c, Ecological studies.

Presoaking Grafts in Vancomycin Does Not Impair Graft-Bone Healing in a Rat Anterior Cruciate Ligament Reconstruction Model.

BACKGROUND: The vancomycin presoaking technique (wherein grafts are treated with a vancomycin solution [VS] for anterior cruciate ligament reconstruction [ACLR]) reduces the infection rate after ACLR. However, the effects of this technique on graft-bone healing have not been fully elucidated. PURPOSE: To investigate the effects of vancomycin presoaking on graft-bone healing in a rat ACLR model. STUDY DESIGN: Controlled laboratory study. METHODS: Long flexor digitorum longus tendons were obtained from 9 Wistar rats, and each was randomly allocated to the normal saline (NS) or VS groups. The grafts were immersed in sterile saline for 30 minutes in the NS group and in a 5-mg/mL VS in the VS group. The presence of time-zero graft bacterial contamination was confirmed, and the grafts were incubated in Fluidised Thioglycollate Broth for 2 weeks. ACLR was performed on the right knees of 65 male Wistar rats using the flexor digitorum longus tendons. Each graft was similarly treated. Biomechanical testing, micro-computed tomography, and histological evaluations were performed 4 and 12 weeks postoperatively. RESULTS: The VS group showed significantly reduced graft contamination at time zero (P = .02). The mean maximum loads to failure were 13.7 ± 8.2 N and 11.6 ± 4.8 N in the NS and VS groups, respectively, at 4 weeks (P = .95); and 23.2 ± 13.2 N and 30.4 ± 18.0 N in the NS and VS groups, respectively, at 12 weeks (P = .35). Regarding micro-computed tomography, the mean bone tunnel volumes were 3.76 ± 0.48 mm3 and 4.40 ± 0.58 mm3 in the NS and VS groups, respectively, at 4 weeks (P = .41); and 3.51 ± 0.38 mm3 and 3.67 ± 0.35 mm3 in the NS and VS groups, respectively, at 12 weeks (P = .54). Histological semiquantitative examination revealed no clear between-group differences at any time point. CONCLUSION: Presoaking grafts in vancomycin in a rat ACLR model demonstrated no discernible adverse effects on short- and midterm biomechanical, radiological, and histological investigations. CLINICAL RELEVANCE: The findings provide guidance for surgeons when considering this technique.

Efficacy of repeated intravenous injection of peramivir against influenza A (H1N1) 2009 virus infection in immunosuppressed mice.

The efficacy of intravenous peramivir against influenza A (H1N1) 2009 virus infection was evaluated in mice in which the immune system was suppressed by cyclophosphamide (CP) treatment. The mortality rate of the vehicle control group was 100%, and the mice lost 20% of their body weight on average by day 13 postinfection (p.i.). Repeated administration of peramivir (40 mg/kg of body weight once a day, given intravenously for 20 days), starting at 1 h p.i., significantly reduced mortality, body weight loss, viral titers, and cytokine production in infected mice compared with results for administration of vehicle (P < 0.01). In addition, repeated administration of peramivir, starting at 24 h, 48 h, or 72 h p.i., also resulted in increases in survival rates and reduction of viral titers in the lungs (P < 0.01). The mean days to death (MDD) of the vehicle group was 14.5 days, while in the groups treated with peramivir starting at 24 h, 48 h, and 72 h p.i., the MDDs were >23.0, 20.9, and 21.8 days, respectively. In comparison, repeated administration of oseltamivir phosphate (5 mg/kg twice a day, given orally for 20 days), starting at 24 h, 48 h, and 72 h p.i., also significantly prevented body weight loss, whereas no significant differences in mortality rates and viral titers in the lungs were observed compared with results for the vehicle group. These data indicated that repeated administration of peramivir was effective in promoting the survival and reducing virus replication in immunosuppressed mice infected with influenza A (H1N1) 2009 virus.