A Comparison of Imaging Outcomes From 2 Weightbearing CT Modalities.

BACKGROUND: The use of weightbearing images to diagnose foot and ankle injuries continues to offer hope for improved insight into pathologies, but weightbearing CT imaging has been limited by availability. The ability to apply force to the lower limb in a horizontal bore CT system may offer an adaptation to currently available imaging systems that provides access to weightbearing images without the acquisition of additional expensive imaging space or equipment. METHODS: In order to determine whether a horizontal CT system could produce the same results as a standing CT, 3 images of one foot from 10 subjects was obtained and standard measures were calculated. Each subject underwent a standing CT scan, a scan in a horizontal bore CT machine while the subject pressed against a pedal with spring resistance and a finally a scan with the foot placed on the pedal but without any pressure. RESULTS: No statistically significant difference between the standing and pedal-based CTs resulted. Navicular height and Meary angle (axial) were statistically different from nonweightbearing for both standing and horizontal systems. The horizontal results were statistically different from nonweightbearing in IM angle, talocalcaneal angle, and talonavicular coverage. No differences from nonweightbearing were found for either system in talar tilt, talocrural angle, or the lateral Meary angle. CONCLUSION: The results in this initial study of normal control subjects suggest that a pedal-based loading mechanism may adapt a horizontal-bore CT system for the acquisition of weightbearing images. CLINICAL RELEVANCE: The ability to acquire a weightbearing CT from a horizontal bore CT machine can make these images more available.

The Rotator Cable Does Not Stress Shield the Crescent Area During Shoulder Abduction.

BACKGROUND: It is accepted by the orthopaedic community that the rotator cable (RCa) acts as a suspension bridge that stress shields the crescent area (CA). The goal of this study was to determine if the RCa does stress shield the CA during shoulder abduction. METHODS: The principal strain magnitude and direction in the RCa and CA and shoulder abduction force were measured in 20 cadaveric specimens. Ten specimens underwent a release of the anterior cable insertion followed by a posterior release. In the other 10, a release of the posterior cable insertion was followed by an anterior release. Testing was performed for the native, single-release, and full-release conditions. The thicknesses of the RCa and CA were measured. RESULTS: Neither the principal strain magnitude nor the strain direction in either the RCa or the CA changed with single or full RCa release (p ≥ 0.493). There were no changes in abduction force after single or full RCa release (p ≥ 0.180). The RCa and CA thicknesses did not differ from one another at any location (p ≥ 0.195). CONCLUSIONS: The RCa does not act as a suspension bridge and does not stress shield the CA. The CA primarily transfers shoulder abduction force to the greater tuberosity. CLINICAL RELEVANCE: The CA is important in force transmission during shoulder abduction, and efforts should be made to restore its continuity with a repair or reconstruction.

Humeral offset as a predictor of outcomes after reverse shoulder arthroplasty.

INTRODUCTION: The Grammont-style reverse shoulder arthroplasty (RSA) relies on medialization and distalization of the shoulder center of rotation. Lateralized designs have recently gained popularity. The amount of lateralization, however, remains a controversial topic. The purpose of this study was to correlate the change in humeral offset (HO) with outcomes and complications following RSA. We hypothesized that a lateralized HO following RSA would be associated with improved range of motion (ROM), better patient-reported outcomes (PROs), and fewer complications. MATERIALS AND METHODS: A consecutive series of 104 patients (109 shoulders) was retrospectively evaluated. All patients underwent primary RSA by 2 shoulder and elbow fellowship-trained orthopedic surgeons at 2 different centers. Inclusion criteria was a primary RSA with at least 1-year follow-up. All patients had the HO measured on a preoperative and a postoperative Grashey radiograph, and the change in HO was calculated (ΔHO = PostHO-PreHO). A negative value was defined as a medialized HO and a positive value as a lateralized HO. ROM and primary outcomes, including forward elevation (FE), external rotation (ER), internal rotation (IR), Subjective Shoulder Value (SSV), and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score, were collected. Complications and revisions were also reported. RESULTS: The mean age was 72 years with a mean follow-up of 22.3 months. The average FE (92° vs. 148°), ER (34° vs. 44°), SSV (35% vs. 87%), and ASES score (37.2 vs. 81.2) increased significantly (all P < .01) compared with preoperative values. The HO was medialized postoperatively in 63 shoulders and lateralized in 46 shoulders. No statistically significant differences in the mean values for postoperative FE (147° vs. 146°, P = .892), ER (43° vs. 45°, P = .582), IR (L3 vs. L3, P = .852), SSV (88% vs. 85%, P = .476), and ASES score (81.3 vs. 81.1, P = .961) were found between the groups. However, there was significantly more improvement in ER in the lateralized HO cohort than the medialized cohort (16° vs. 7°, P = .033). Six shoulders, 5 medialized and 1 lateralized HO, demonstrated scapular notching and remained asymptomatic. Five shoulders, 4 medialized and 1 lateralized HO, experienced at least 1 instability incident, and 2 shoulders with medialized HO had an acromion/scapular spine fracture. Overall, 2 shoulders with medialized HO underwent revision surgery because of instability. CONCLUSIONS: Although RSA provides significant improvement in ROM and PROs regardless of postoperative HO, restoring baseline HO or lateralization beyond baseline may be favorable for improving ER and decreasing complications following RSA.

Discovery and Characterization of Potent Dual P-Glycoprotein and CYP3A4 Inhibitors: Design, Synthesis, Cryo-EM Analysis, and Biological Evaluations.

Targeted concurrent inhibition of intestinal drug efflux transporter P-glycoprotein (P-gp) and drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is a promising approach to improve oral bioavailability of their common substrates such as docetaxel, while avoiding side effects arising from their pan inhibitions. Herein, we report the discovery and characterization of potent small molecule inhibitors of P-gp and CYP3A4 with encequidar (minimally absorbed P-gp inhibitor) as a starting point for optimization. To aid in the design of these dual inhibitors, we solved the high-resolution cryo-EM structure of encequidar bound to human P-gp. The structure guided us to prudently decorate the encequidar scaffold with CYP3A4 pharmacophores, leading to the identification of several analogues with dual potency against P-gp and CYP3A4. In vivo, dual P-gp and CYP3A4 inhibitor 3a improved the oral absorption of docetaxel by 3-fold as compared to vehicle, while 3a itself remained poorly absorbed.

Locating the rotator cable during subacromial arthroscopy: bursal- and articular-sided anatomy.

BACKGROUND: The rotator cable (RCa) is an important articular-sided structure of the cuff capsular complex that helps prevent suture pull out during rotator cuff repairs (RCRs) and plays a role in force transmission. Yet, the RCa cannot be located during bursal-sided RCRs. The purpose of this study is to develop a method to locate the RCa in the subacromial space and compare its bursal- and articular-sided dimensions. METHODS: In 20 fresh-frozen cadaveric specimens, the RCa was found from the articular side, outlined with stitches, and then evaluated from the bursal side using an easily identifiable reference point, the intersection of a line bisecting the supraspinatus (SS) tendon and posterior SS myotendinous junction (MTJ). Four bursal-sided lengths were measured on the SS-bisecting line as well as the RCa's outside anteroposterior base. For the articular-sided measurements, the rotator cuff capsular complex was detached from bone and optically scanned creating 3D solid models. Using the 3D models, 4 articular-sided lengths were made, including the RCa's inside and outside anteroposterior base. RESULTS: The RCa's medial arch was located 9.9 ± 5.6 mm from the reference point in 10 intact specimens and 4.1 ± 2.4 mm in 10 torn specimens (P = .007). The RCa's width was 10.9 ± 2.1 mm, and the distance from the lateral edge of the RCa to the lateral SS insertion was 13.9 ± 4.8 mm. The bursal- and articular-sided outside anteroposterior base measured 48.1 ± 6.4 mm and 49.6 ± 6.5 mm, respectively (P = .268). The average inside anteroposterior base measurement was 37.3 ± 5.9 mm. DISCUSSION: The medial arch of the RCa can be reliably located during subacromial arthroscopy using the reference point, analogous to the posterior SS MTJ. The RCa is located 10 mm in intact and 4 mm in torn tendons (P = .007) from the posterior SS MTJ. If the above 6-mm shift in location of the RCa is not taken into consideration during rotator cuff suture placement, it could negatively affect time zero repair strength. The inside anteroposterior base of the RCa measures on average 37 mm; therefore, rotator cuff tears measuring >37 mm are at risk of rupturing part or all of the RCa's 2 humeral attachments, which if not recognized and addressed could impact postoperative function.

Discovery of Encequidar, First-in-Class Intestine Specific P-glycoprotein Inhibitor.

Many chemotherapeutics, such as paclitaxel, are administered intravenously as they suffer from poor oral bioavailability, partly because of efflux mechanism of P-glycoprotein in the intestinal epithelium. To date, no drug has been approved by the U.S. Food and Drug Administration (FDA) that selectively blocks this efflux pump. We sought to identify a compound that selectively inhibits P-glycoprotein in the gastrointestinal mucosa with poor oral bioavailability, thus eliminating the issues such as bone marrow toxicity associated with systemic inhibition of P-glycoprotein. Here, we describe the discovery of highly potent, selective, and poorly orally bioavailable P-glycoprotein inhibitor 14 (encequidar). Clinically, encequidar was found to be well tolerated and minimally absorbed; and importantly, it enabled the oral delivery of paclitaxel.

Partial Distal Biceps Avulsion Results in a Significant Loss of Supination Force.

BACKGROUND: Partial avulsions of the short and/or long head of the distal biceps tendon cause pain and loss of strength. The goal of the present study was to quantify the loss of supination and flexion strength following a series of surgical releases designed to simulate partial and complete short and long head traumatic avulsions. METHODS: Mechanical testing was performed to measure supination moment arms and flexion force efficiency on 18 adult fresh-frozen specimens in pronation, neutral, and supination. The distal biceps footprint length was divided into 4 equal segments. In 9 specimens (the distal-first group), the tendon was partially cut starting distally by releasing 25%, 50%, and 75% of the insertion site. In the other 9 specimens (the proximal-first group), the releases started proximally. Mechanical testing was performed before and after each release. RESULTS: Significant decreases in the supination moment arm occurred after a 75% release in the distal-first release group; the decrease was 24% in pronation (p = 0.003) and 10% in neutral (p = 0.043). No significant differences in the supination moment arm (p ≥ 0.079) or in flexion force efficiency (p ≥ 0.058) occurred in the proximal-first group. CONCLUSIONS: A simulated complete short head avulsion significantly decreased the supination moment arm and therefore supination strength. CLINICAL RELEVANCE: A mechanical case can be made for repair of partial distal biceps tendon avulsions when the rupture involves ≥75% of the distal insertion site.

HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model.

Objective: Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma, owing to the presence of the blood-brain barrier and the activity of P-gp, which pumps its substrate back into the systemic circulation. The aim of the present study was to develop an intravenous formulation of HM30181A (HM) to inhibit P-gp in the brain to effectively deliver paclitaxel (PTX) for the treatment of malignant glioma. Methods: Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies: i) spray-drying [polyvinlypyrrolidone (PVP)-HM] and ii) solvent evaporation [HP-ß-cyclodextrin (cyclodextrin)-HM]. The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells. Blood and brain pharmacokinetic parameters were also determined, and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model. Results: Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro, cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM. Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg, and the mice began to lose weight at doses above this level. Cyclodextrin-HM (10 mg/kg) administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model, according to both tumor volume measurement and survival time (P < 0.05). Conclusions: In a mouse orthotopic brain tumor model, the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.

The effect of tendon rotation on distal biceps repair.

BACKGROUND: The distal biceps tendon externally rotates from proximal to distal before inserting onto the radius. Our hypothesis is that an externally rotated (anatomic) repair would re-create native supination moment arm and flexion force, whereas an internally rotated (nonanatomic) repair would result in reduced force transmission. METHODS: The mechanical tests performed in this study measured isometric moment arms and elbow flexion force using a validated elbow simulator as previously published. Mechanical testing was performed on 8 native cadaveric elbows (61 ± 15 years). The distal biceps tendons in all specimens were then incised from their footprint and repaired with anatomic and nonanatomic tendon rotations. After each repair, the specimens were retested. The repair sequence was randomly assigned. RESULTS: Gross observation showed repair site bunching with the nonanatomic repairs. There was no statistical difference in the moment arms between the native, anatomic, and nonanatomic rotations for the 3 forearm angles (P ≥ .352). Analysis showed no statistical difference in flexion force ratio for the elbow at 90° (P ≥ .283). DISCUSSION: The study showed that biceps tendon rotation does not play a role in supination moment arm or flexion force. Twisting the distal biceps tendon around the tendon axis does not change the direction of its applied force on the tuberosity. Tendon bunching in nonanatomic reattachments increases repair site width, which may lead to tendon-ulnar impingement during forearm rotation.

Clinical and functional impairment after nonoperative treatment of distal biceps ruptures.

BACKGROUND: Clinical and functional impairment after nonoperative treatment of distal biceps ruptures is not well understood. The goal of this study was to measure patients' perceived disability, kinematic adjustment, and forearm supination power after nonoperative treatment of distal biceps ruptures. METHODS: Fourteen individuals after nonoperative treatment of distal biceps ruptures were matched to a control group of 18 uninjured volunteers. Both groups prospectively completed the Disabilities of the Arm, Shoulder and Hand (DASH), Single Assessment Numerical Evaluation (SANE), and Biceps Disability Questionnaire. Both performed a new timed isotonic supination test that was designed to simulate activities of daily life. The isotonic torque dynamometer measures the supination arc, center of supination arc, torque, angular velocity, and power. Motion analysis quantifies forearm and shoulder contributions to the arc of supination. RESULTS: The nonoperative treated group's DASH (23.2 ± 10.3) and SANE (59.6 ± 16.2) scores demonstrated a clinical meaningful impairment. The control group showed no significant differences in kinematic values between dominant and nondominant arms (P = .854). The nonoperative biceps ruptured arms, compared with their uninjured arms, changed supination motion by decreasing the supination arc (P ≤ .036), shifting the center of supination arc to a more pronated position (P ≤ .030), and increasing the shoulder contribution to rotation (P ≤ .001); despite this adaptation, their average corrected power of supination decreased by 47% (P = .001). CONCLUSION: Patients should understand that nonoperative treatment for distal biceps ruptures will result in varying degrees of functional loss as measured by the DASH, SANE, and Biceps Disability Questionnaire, change their supination kinematics during repetitive tasks, and that they will lose 47% of their supination power.

KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma.

PURPOSE: A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood-brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity. METHODS: KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma. RESULTS: In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture. CONCLUSIONS: The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model.

Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361).

The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy. Compound 2 is a phase 1 clinical trial candidate that is likely to provide a first in class treatment of malignant glioblastoma and induces 30% long-term complete tumor remission in animal models. The discovery strategy for these compounds iteratively utilized molecular modeling, along with the synthesis and testing of increasingly elaborated proof of concept compounds, until the final clinical candidates were arrived at. This was followed with mechanism of action (MOA) studies that revealed tubulin polymerization inhibition as the second MOA.