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.

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.

iPSC-derived tenocytes seeded on microgrooved 3D printed scaffolds for Achilles tendon regeneration.

Tendons and ligaments have a poor innate healing capacity, yet account for 50% of musculoskeletal injuries in the United States. Full structure and function restoration postinjury remains an unmet clinical need. This study aimed to assess the application of novel three dimensional (3D) printed scaffolds and induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) overexpressing the transcription factor Scleraxis (SCX, iMSCSCX+ ) as a new strategy for tendon defect repair. The polycaprolactone (PCL) scaffolds were fabricated by extrusion through a patterned nozzle or conventional round nozzle. Scaffolds were seeded with iMSCSCX+ and outcomes were assessed in vitro via gene expression analysis and immunofluorescence. In vivo, rat Achilles tendon defects were repaired with iMSCSCX+ -seeded microgrooved scaffolds, microgrooved scaffolds only, or suture only and assessed via gait, gene expression, biomechanical testing, histology, and immunofluorescence. iMSCSCX+ -seeded on microgrooved scaffolds showed upregulation of tendon markers and increased organization and linearity of cells compared to non-patterned scaffolds in vitro. In vivo gait analysis showed improvement in the Scaffold + iMSCSCX+ -treated group compared to the controls. Tensile testing of the tendons demonstrated improved biomechanical properties of the Scaffold + iMSCSCX+ group compared with the controls. Histology and immunofluorescence demonstrated more regular tissue formation in the Scaffold + iMSCSCX+ group. This study demonstrates the potential of 3D-printed scaffolds with cell-instructive surface topography seeded with iMSCSCX+ as an approach to tendon defect repair. Further studies of cell-scaffold constructs can potentially revolutionize tendon reconstruction by advancing the application of 3D printing-based technologies toward patient-specific therapies that improve healing and functional outcomes at both the cellular and tissue level.

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.

Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection.

Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.

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.

[Corporate Efforts to Research and Develop Therapeutic Agents for Infectious Diseases That Threaten Human].

Overcoming serious infectious diseases such as malaria, tuberculosis, and other neglected tropical diseases (NTDs) that threaten human life around the world is an important issue in global health. Most of these diseases are concentrated in developing and low-income countries, and in order to reinforce drug discovery activities, pharmaceutical companies are actively promoting industry-academia-government partnerships and utilizing funds to stimulate global health activities. In this presentation, three examples of our drug discovery activities are introduced. The first is participation in the Booster project led by Drugs for Neglected Diseases initiative (DNDi) aimed at creating therapeutic agents for leishmaniasis and Chagas disease, an effort supported by the Global Health Innovative Technology (GHIT) Fund. As domestic and overseas pharmaceutical companies participate in the project and provide their own compounds, it is possible to obtain structure-activity relationship information in a short period of time and improve compound potency. We collaborated with DNDi to create a lead compound from one hit compound, and contributed to further enhancement of its activity. The remaining two are collaborations with academia for the creation of new therapeutic agents or vaccines: a joint research project with Hokkaido University Research Center for Zoonosis Control for emerging viral diseases, and a collaboration with Nagasaki University in malaria. In each case, our researchers were based at the university, establishing close working collaborations with the university researchers. Novel solutions for serious infectious diseases are expected by the combination of the high-level basic research capabilities of academia and the drug discovery know-how and original compound libraries possessed by pharmaceutical companies.

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.

Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against H5 Highly Pathogenic Avian Influenza Virus Infection.

Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class of inhibitors for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but it has not yet been fully characterized. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants, was assessed in vitro. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested in comparison with seasonal and other zoonotic strains. Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-h delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival. In conclusion, BXM has a potent antiviral efficacy against H5 HPAIV infections.

Collaborative virtual screening to elaborate an imidazo[1,2-a]pyridine hit series for visceral leishmaniasis.

An innovative pre-competitive virtual screening collaboration was engaged to validate and subsequently explore an imidazo[1,2-a]pyridine screening hit for visceral leishmaniasis. In silico probing of five proprietary pharmaceutical company libraries enabled rapid expansion of the hit chemotype, alleviating initial concerns about the core chemical structure while simultaneously improving antiparasitic activity and selectivity index relative to the background cell line. Subsequent hit optimization informed by the structure-activity relationship enabled by this virtual screening allowed thorough investigation of the pharmacophore, opening avenues for further improvement and optimization of the chemical series.

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.

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.

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.

The antiviral effects of baloxavir marboxil against influenza A virus infection in ferrets.

BACKGROUND: Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients. OBJECTIVES: To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets. METHODS: Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM. RESULTS: The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4. CONCLUSIONS: The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission.

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.

Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease.

The medicinal chemistry and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be critical for the plasma protein binding effect in vitro, and the CAB-N analogue 2v exhibited reasonable total clearance (CLtot). More importantly, compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.