Reliability of the Dorsal Tangential View in Assessment of Distal Radioulnar Joint Reduction in the Neutral, Pronated, and Supinated Positions in a Cadaver Model.

PURPOSE: Intraoperative assessment of distal radioulnar joint (DRUJ) alignment is often based on lateral radiographs whose interpretation is dependent upon positioning the forearm in neutral rotation. The dorsal tangential view (DTV) is a near-axial view of the dorsal wrist used in assessing dorsal screw penetration during radius fixation. The purpose of this study was to determine whether the DTV can also reliably assess DRUJ alignment in multiple forearm positions. METHODS: Four transhumeral cadaveric specimens were used to simulate an unstable DRUJ. The stabilizing soft tissue structures of the DRUJ were sectioned. Fluoroscopic DTV images were obtained with the DRUJ of each specimen held in 5 positions: dorsally dislocated, dorsally subluxated, reduced, volarly subluxated, and volarly dislocated. In each position, images were taken with the forearm in neutral rotation, full pronation, and full supination. Three observers independently assessed DRUJ position on DTV images. Intra- and interobserver reliability were assessed in each forearm position. RESULTS: Observers correctly identified DRUJ position as reduced, volarly malreduced, or dorsally malreduced on 94% of the DTV images (97%, 95%, and 92% in the neutral, supinated, and pronated forearm positions, respectively). Weighted kappa values for intraobserver reliability were 0.965, 0.964, and 0.965 for the 3 observers. The mean kappas for intraobserver reliability were 1.000, 0.967, and 0.930 with the forearm in neutral, supinated, and pronated positions, respectively. Weighted kappa values for interobserver reliability between paired observers were 0.948, 0.912, and 0.929. The mean kappa for interobserver reliability was 0.926, 0.931, and 0.930 for the forearm in neutral, supinated, and pronated positions, respectively. CONCLUSIONS: The DTV reliably demonstrated the position of the DRUJ independent of forearm rotation in a cadaveric model. CLINICAL RELEVANCE: Surgeons may consider the DTV as another tool for fluoroscopic verification of the DRUJ reduction in the operating room or clinic.

Masquelet Reconstruction for Posttraumatic Segmental Bone Defects in the Forearm.

PURPOSE: The Masquelet technique is a procedure increasingly utilized for addressing segmental bone defects. The technique involves staged procedures consisting of bone debridement and temporary spacer placement to induce membrane formation, followed by delayed bone grafting. This report summarizes our center's experience with the Masquelet technique to reconstruct bone loss exclusively in the forearm. METHODS: We reviewed all cases in which the Masquelet technique was used to reconstruct segmental bone defects in the forearm resulting from acute trauma or nonunion, with or without infection, between 2014 and 2017 at a level-1 trauma center. Injury mechanism, prior surgeries, extent of bone defect, and demographic data were collected. Union was assessed along with treatment-related complications or reoperations. RESULTS: We identified 9 patients with segmental bony defects in the forearm treated with the Masquelet technique. Among this cohort, 5 patients had bone defects associated with acute open fractures and 4 patients presented with nonunion (1 atrophic and 3 infected nonunions). The median bony defect was 4.7 cm (range, 1.7-5.4 cm) at the time of grafting. Second stage grafting was performed with Reamer Irrigator Aspirator autograft from the femur in 8 patients and iliac crest bone cancellous graft in 1 patient. Union was achieved in all 9 patients. Six patients achieved union by 3-month follow-up, 2 patients by 6 months, and 1 patient by 12 months. One patient required a reoperation for plate fracture prior to union treated with revision internal fixation and grafting. CONCLUSIONS: The Masquelet technique effectively reconstructed traumatic and posttraumatic segmental defects in the forearm with a low incidence of complication. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Treatment of Radial Head Fractures and Need for Revision Procedures at 1 and 2 Years.

PURPOSE: Optimal treatment strategies for radial head fractures remain a subject of debate. We examined national practice patterns in the management of radial head fractures to determine rates of surgical treatment, type of surgery employed, and the incidence of reoperation. METHODS: Between 2007 and 2011, we identified patients with radial head fractures along with their associated injuries by International Classification of Diseases, Ninth Revision codes in a national database of orthopedic insurance records. For those who underwent surgery, the type of intervention was identified and each patient was observed to determine whether a subsequent procedure was needed by 1 and 2 years. Chi-square analysis was performed to make comparisons between groups. RESULTS: A total of 58,404 radial head fractures were identified between 2007 and 2011; of these, 2,981 underwent surgical treatment (5.1%). Rates of surgical intervention were significantly higher in the context of associated injuries. Among the 2,981 radial head fractures treated surgically, 57.1% underwent open reduction internal fixation (ORIF), 37.9% were treated with radial head arthroplasty, and 4.9% underwent radial head excision. When the surgically treated radial head fracture was associated with a coronoid fracture, elbow dislocation, or proximal ulna fracture, 64.2%, 54.3%, and 47.2% were treated with arthroplasty, respectively, compared with 32.6%, 41.9%, and 52.6% treated with ORIF, respectively. After initial surgical treatment, 12.7% and 14.4% of radial head fractures that underwent ORIF required a secondary surgery at 1 and 2 years, respectively, compared with 8.6% and 10.7% of radial head arthroplasties and 8.3% and 8.4% of resections. CONCLUSIONS: Rates of arthroplasty were significantly higher in the context of associated injury, particularly in the setting of a coronoid fracture or elbow dislocation. Fractures initially treated with ORIF had a higher rate of revision surgery at both 1 and 2 years after the index procedure compared with arthroplasty. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability.

BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties.

A Cadaver Investigation of Screw Purchase With 2 Retrograde Techniques for Capitolunate Arthrodesis.

PURPOSE: To examine the hypothesis that the amount of bone purchase within the lunate is greater when using a technique for intermetacarpal retrograde screw placement across the capitolunate joint than when using a dorsal capitate technique. METHODS: Seven fresh cadaver limbs were dissected. We exposed the carpus and scaphoidectomy and performed selective capitolunate decortication. We compared the technique of dorsal capitate placement of headless compression screws with intermetacarpal placement by measuring the depth of purchase in the lunate. RESULTS: Drill hole depths in the lunate were greater using the intermetacarpal technique versus the dorsal capitate technique; the average depth was 9.0 and 6.4 mm, respectively. The calculated number of threads was also greater with the intermetacarpal technique than with the dorsal capitate technique (15 vs 9 threads, respectively). CONCLUSIONS: The intermetacarpal technique for retrograde headless compression screw placement in a capitolunate arthrodesis provided a greater depth of purchase in the lunate portion of the construct. It also afforded more ease of placement than previously described antegrade techniques without the risk of hardware migration into the radiocarpal joint. CLINICAL RELEVANCE: The knowledge gained from this study may help guide surgeons to choose a technique for retrograde placement of headless compression screws in capitolunate arthrodesis to gain better purchase within the lunate.

Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834.

SAR studies focused on improving the pharmacokinetic (PK) properties of the previously reported potent and selective Btk inhibitor CGI-1746 (1) resulted in the clinical candidate GDC-0834 (2), which retained the potency and selectivity of CGI-1746, but with much improved PK in preclinical animal models. Structure based design efforts drove this work as modifications to 1 were investigated at both the solvent exposed region as well as 'H3 binding pocket'. However, in vitro metabolic evaluation of 2 revealed a non CYP-mediated metabolic process that was more prevalent in human than preclinical species (mouse, rat, dog, cyno), leading to a high-level of uncertainly in predicting human pharmacokinetics. Due to its promising potency, selectivity, and preclinical efficacy, a single dose IND was filed and 2 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, 2 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure. This information informed the back-up program and discovery of improved inhibitors.

Management of gunshot wounds near the elbow: experiences at a high-volume level I trauma center.

BACKGROUND: Gunshot-related fractures near the elbow are challenging, and available data to guide the practitioner are lacking. This report analyzes injury patterns and treatment strategies in a case series from a high-volume urban trauma center. METHODS: All periarticular gunshot fractures near the elbow treated at a level 1 trauma center from 2014 to 2018 were retrospectively reviewed. Fracture location, patient demographics, concomitant injuries, treatment modalities, and complications were analyzed. RESULTS: Twenty-four patients were identified. All patients received prophylactic antibiotics upon admission and underwent urgent surgical debridement. Open reduction and internal fixation (ORIF) was performed with initial debridement in 22 of 24 patients. Seven patients sustained distal humerus fractures, 10 patients sustained isolated proximal ulna or proximal radius fractures, and seven had combined fracture patterns. Eleven patients presented with nerve palsy, and two had transected nerves. Two patients had vascular injury requiring repair. One patient required a temporary elbow-spanning external fixator and underwent staged debridement followed by ORIF. One patient with a grade IIIC fracture developed a deep infection that precluded ORIF. One patient required revision ORIF due to fracture displacement. CONCLUSIONS: This investigation reports on management of ballistic fractures near the elbow at a busy urban level I trauma center. Our management centered on rapid debridement, early definitive fixation, and intravenous antibiotic administration. We report on associated neurovascular injury, bone loss, and other challenges in this patient population. Level of evidence: IV.

Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis.

Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1ß and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.

Accuracy and Safety of Non-Image Guided Trigger Finger Injections: A Cadaveric Study.

BACKGROUND: Stenosing flexor tenosynovitis is commonly treated by injection of corticosteroids into the flexor tendon sheath. However, there is no consensus in the literature regarding the optimal technique, specifically when not utilizing ultrasound guidance. Here, we present a cadaver study in which 3 common techniques of flexor sheath injection were compared with regard to their accuracy and safety profiles. METHODS: Fifteen fresh-frozen cadaver hands (60 digits) were evenly divided into 3 groups (20 digits per group). Digits in each group were injected with methylene blue dye using 1 of the 3 techniques (palmar-to-bone, palmar supra-tendinous, and mid-axial). The fingers were then dissected and were inspected for location of dye, as well as injury to tendon or digital nerves. RESULTS: The mid-axial technique demonstrated the greatest accuracy with the highest rate of all intra-sheath injection, 15 of 20 digits (75%), while the palmar-to-bone technique produced the most combined intra- and extra-sheath injections, 13 of 20 digits, (65%) and the palmar supra-tendinous technique resulted in the most all extra-sheath injections, 9 of 20 digits (45%). The difference in rates of all intra-sheath injection was significant (P = .01). The mid-axial technique also produced the fewest intra-tendinous injections 0 of 20, although this result did not reach statistical significance (P = .15). CONCLUSIONS: Compared to other common non-image guided flexor tendon sheath injection techniques, the mid-axial injection technique was found to be the most accurate in producing all intra-sheath injection and least likely to result in intra-tendinous injection.

Radial Collateral Ligament Injuries of the Thumb Metacarpophalangeal Joint.

PURPOSE OF REVIEW: Injuries to the radial collateral ligament (RCL) of the thumb are thought to be relatively uncommon, especially when compared to the ulnar collateral ligament. However, the radial collateral ligament is increasingly recognized as critical for the overall stability of the thumb metacarpophalangeal joint. This article sets out to provide a comprehensive review of RCL injuries of the thumb MCP joint, including epidemiology, biomechanics, diagnosis, and treatment. RECENT FINDINGS: Although traditionally thought to respond well to conservative management, especially when compared to injuries to the ulnar collateral ligament, there is mounting evidence that chronic RCL injury leads to thumb metacarpophalangeal joint instability and can accelerate post-traumatic joint degeneration. Thus, much of the recent literature details surgical treatment options for radial collateral ligament injury, including repair and reconstruction. While incomplete tears of the thumb RCL respond well to immobilization, complete tears should generally be treated with operative management, either direct repair or anatomic reconstruction, depending on tissue quality. Even subacute and chronic injuries may be amenable to direct repair, with good to excellent outcomes, including in high-demand patient populations, such as professional athletes.

Sacral Insufficiency Fracture Following Short-Segment Lumbosacral Fusion: Case Series and Review of the Literature.

STUDY DESIGN: Retrospective case series. OBJECTIVE: Sacral insufficiency fracture is a rare and serious complication following lumbar spine instrumented fusion. The purpose of this study was to describe the patient characteristics, presentation, evaluation, treatment options, and outcomes for patients with sacral insufficiency fracture after short-segment lumbosacral fusion. METHODS: Six patients from our institutional database and 16 patients from literature review were identified with a sacral insufficiency fracture after short-segment (L4-S1 or L5-S1) lumbar fusion within 1 year of surgery. RESULTS: Patients were 55% female with a mean age of 58 years and body mass index of 30 kg/m2. Osteoporosis or osteopenia was the most common comorbidity (85%). Half of patients sustained a sacral fracture after surgery from a posterior approach, while the others had anterior or anterior-posterior surgery. Mean time to fracture was 42 days with patients clinically presenting with new sacral pain (86%), radiculopathy (60%), or neurologic deficit (5%). Ultimately, 73% of patients underwent operative fixation often involving extension of the construct (75%) and fusion to the pelvis (69%). Men (P = .02) and patients with new radicular pain or neurologic deficit (P = .01) were more likely to undergo revision surgical treatment while women over 50 years of age were more likely to be treated conservatively (P = .003). CONCLUSIONS: Spine surgeons should monitor for sacral insufficiency fracture as a source of new-onset pain in the postoperative period in patients with a short segment fusion to the sacrum. The recognition of this complication should prompt an assessment of bone health and management of underlying bone fragility.

Generalized response of a sphere embedded in a viscoelastic medium excited by an ultrasonic radiation force.

The response of an embedded sphere in a viscoelastic medium excited by acoustic radiation force has been studied in both the time- and frequency-domains. This model is important because it can be used to characterize the viscoelastic properties of the medium by fitting the response to the theoretical model. The Kelvin-Voigt model has been used exclusively in these models. An extension to the previously reported models is described so that any viscoelastic rheological model can be used. This theoretical development describes the generalized embedded sphere response both in the time and frequency domains. Comparing the results from derivations in both domains showed very good agreement with a median absolute error (MAE) ranging from 0.0044 to 0.0072. Good agreement is demonstrated with finite element model simulations and the theory with a MAE of 0.006. Lastly, results for characterization of gelatin and rubber materials with the new theory are shown where the MAE values were used to determine which rheological model best describes the measured responses.

VoroCrust: Voronoi Meshing Without Clipping.

Polyhedral meshes are increasingly becoming an attractive option with particular advantages over traditional meshes for certain applications. What has been missing is a robust polyhedral meshing algorithm that can handle broad classes of domains exhibiting arbitrary curved boundaries and sharp features. In addition, the power of primal-dual mesh pairs, exemplified by Voronoi-Delaunay meshes, has been recognized as an important ingredient in numerous formulations. The VoroCrust algorithm is the first provably correct algorithm for conforming Voronoi meshing for non-convex and possibly non-manifold domains with guarantees on the quality of both surface and volume elements. A robust refinement process estimates a suitable sizing field that enables the careful placement of Voronoi seeds across the surface circumventing the need for clipping and avoiding its many drawbacks. The algorithm has the flexibility of filling the interior by either structured or random samples, while all sharp features are preserved in the output mesh. We demonstrate the capabilities of the algorithm on a variety of models and compare against state-of-the-art polyhedral meshing methods based on clipped Voronoi cells establishing the clear advantage of VoroCrust output.

Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases.

Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.

Imidazo[1,2-a]pyrazine diaryl ureas: inhibitors of the receptor tyrosine kinase EphB4.

Inhibition of receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs) has been validated by recently launched small molecules Sutent and Nexavar, both of which display activities against several angiogenesis-related RTKs. EphB4, a receptor tyrosine kinase (RTK) involved in the processes of embryogenesis and angiogenesis, has been shown to be aberrantly up regulated in many cancer types such as breast, lung, bladder and prostate. We propose that inhibition of EphB4 in addition to other validated RTKs would enhance the anti-angiogenic effect and ultimately result in more pronounced anti-cancer efficacy. Herein we report the discovery and SAR of a novel series of imidazo[1,2-a]pyrazine diarylureas that show nanomolar potency for the EphB4 receptor, in addition to potent activity against several other RTKs.

Bedrock nitrogen weathering stimulates biological nitrogen fixation.

Global ecosystem models suggest that bedrock nitrogen (N) weathering contributes 10-20% of total N inputs to the natural terrestrial biosphere and >38% of ecosystem N supplies in temperate forests specifically. Yet, the role of rock N weathering in shaping ecological processes and biogeochemical fluxes is largely unknown. Here, we show that temperate forest ecosystems underlain by N-rich bedrock exhibit higher free-living N fixation rates than similar forests residing on N-poor parent materials, across sites experiencing a range of climate and tectonic regimes. This seemingly counterintuitive result can be explained by increased accumulation of soil C and P in high bedrock N sites, resulting in increased energy inputs and nutrient supplies to N fixing microorganisms. Our findings advance a novel ecosystem biogeochemical framework that recognizes long-term plant-soil-microbe feedbacks in shaping biogeochemical processes, with potentially widespread implications given the global distribution of bedrock N across Earth's terrestrial biomes.

Effect of initial emergency room imaging choice on time to hip reduction and repeat imaging.

OBJECTIVES: Hip dislocations are highly morbid injuries necessitating prompt reduction and post-reduction assessment for fracture and incarcerated fragments. Recent literature has questioned the need for initial pelvic radiographs for acute trauma patients, resulting in computed tomography (CT) scans as the initial evaluation. This study investigates the relationship between choice of pre-reduction imaging and treatment of acute hip dislocations. DESIGN: Retrospective Case-Control. SETTING: Single Academic Level I Trauma Center. METHODS: All acute hip dislocations from 2011 to 2016 were reviewed. Exclusion criteria were diagnosis of dislocation at another facility, death prior to reduction, emergent surgical or ICU intervention, and periprosthetic dislocation. Patients were grouped by those with only a radiograph prior to reduction, Group I, versus those with a pre-reduction CT scan, Group II. The primary outcomes were time to reduction and the acquisition of a second CT scan. RESULTS: Of the 123 hip dislocations identified, 35 patients were excluded, mostly for transfer with a known dislocation. Group I included 29 patients and Group II included 59 patients. The mean time to reduction was 74 min in Group I and 129 min in Group II for a difference of 55 min (p < 0.001). The rate of repeat CT scan was 0 in Group I versus 48 (81%) in Group II (p < 0.001). CONCLUSION: Initial trauma pelvic radiography prior to CT is still important in the setting of suspected hip pathology to decrease time to hip reduction and unnecessary radiation exposure. LEVEL OF EVIDENCE: Prognostic Level III.

Homogeneous BTK Occupancy Assay for Pharmacodynamic Assessment of Tirabrutinib (GS-4059/ONO-4059) Target Engagement.

Bruton's tyrosine kinase (BTK) is a clinically validated target for B-cell leukemias and lymphomas with FDA-approved small-molecule inhibitors ibrutinib and acalabrutinib. Tirabrutinib (GS-4059/ONO-4059, Gilead Sciences, Inc., Foster City, CA) is a second-generation, potent, selective, irreversible BTK inhibitor in clinical development for lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). An accurate pharmacodynamic assay to assess tirabrutinib target coverage in phase 1/2 clinical studies will inform dose and schedule selection for advanced clinical evaluation. We developed a novel duplex homogeneous BTK occupancy assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) to measure free and total BTK levels in a multiplexed format. The dual-wavelength emission property of terbium-conjugated anti-BTK antibody served as the energy donor for two fluorescent energy acceptors with distinct excitation and emission spectra. The assay was characterized and qualified using full-length purified recombinant human BTK protein and peripheral blood mononuclear cells derived from healthy volunteers and patients with CLL. We demonstrated assay utility using cells derived from lymph node and bone marrow samples from patients with CLL and DLBCL. Our TR-FRET-based BTK occupancy assay provides accurate, quantitative assessment of BTK occupancy in the clinical trial program for tirabrutinib and is in use in ongoing clinical studies.

Sampling Conditions for Conforming Voronoi Meshing by the VoroCrust Algorithm.

We study the problem of decomposing a volume with a smooth boundary into a collection of Voronoi cells. Unlike the dual problem of conforming Delaunay meshing, a principled solution to this problem for generic smooth surfaces remained elusive. VoroCrust leverages ideas from weighted α-shapes and the power crust algorithm to produce unweighted Voronoi cells conforming to the surface, yielding the first provably-correct algorithm for this problem. Given a κ-sparse ε-sample, we work with the balls of radius δ times the local feature size centered at each sample. The corners of the union of these balls on both sides of the surface are the Voronoi sites and the interface of their cells is a watertight surface reconstruction embedded in the dual shape of the union of balls. With the surface protected, the enclosed volume can be further decomposed by generating more sites inside it. Compared to clipping-based algorithms, VoroCrust cells are full Voronoi cells, with convexity and fatness guarantees. Compared to the power crust algorithm, VoroCrust cells are not filtered, are unweighted, and offer greater flexibility in meshing the enclosed volume by either structured or randomly genenerated samples.

Discovery of Potent and Selective Tricyclic Inhibitors of Bruton's Tyrosine Kinase with Improved Druglike Properties.

In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis.