Effects of Rifampicin On Pyrotinib Maleate Pharmacokinetics In Healthy Subjects

Purpose: Pyrotinib (PTN) is primarily metabolized by cytochrome P450 (CYP)3A4 isozyme. Rifampicin (RIF) is a strong CYP3A4 inducer. Thus, the effect of oral RIF on PTN pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered.Method: This phase I, open-label study investigated the effects of steady-state RIF administration on single-dose PK of PTN, in 18 healthy participants who received PTN 400 mg single doses on days 1 and 13, and were administrated with RIF 600 mg qd on days 6-16. Each dose for RIF was administrated on an empty stomach, PTN were administrated orally in the morning 30 min after the start of the standard meal. Serial PK samples for PTN were collected on day 1 and day 13. Plasma PTN PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were generated by the mixed-effected model for within-subject treatment comparisons. Safety assessments were performed throughout the study.Results: Eighteen subjects were enrolled and 15 completed the study. RIF significantly reduced PTN exposure: GMRs (90 % CI) for PTN + RIF versus PTN alone were 0.04 (0.034,0.049), 0.04 (0.037,0.054), and 0.11 (0.09,0.124) for area under the curve from time zero to time of last quantifiable concentration (AUC0-t), area under the curve from time zero to infinity (AUC0-∞ ), and maximum observed plasma concentration(Cmax), respectively. PTN alone and co-administered with RIF was well tolerated.Conclusion: Concurrent administration of PTN and RIF was associated with significantly decreased systemic exposure to PTN. The findings suggest that concomitant strong CYP3A4 inducers should be avoided during PTN treatment. Concurrent administration of PTN and RIF was well tolerated.

Biomechanical Comparison of Anatomic Restoration of the Ulnar Footprint vs Traditional Ulnar Tunnels in Ulnar Collateral Ligament Reconstruction

Background: Current techniques for ulnar collateral ligament (UCL) reconstruction do not reproduce the anatomic ulnar footprint of the UCL. The purpose of this study was to describe a novel UCL reconstruction technique that utilizes proximal-to-distal ulnar bone tunnels to better re-create the anatomy of the UCL and to compare the biomechanical profile at time zero among this technique, the native UCL, and the traditional docking technique. Hypothesis: The biomechanical profile of the anatomic technique is similar to the native UCL and traditional docking technique. Study Design: Controlled laboratory study. Methods: Ten matched cadaveric elbows were potted with the forearm in neutral rotation. The palmaris longus tendon graft was harvested, and bones were sectioned 14 cm proximal and distal to the elbow joint. Specimen testing included (1) native UCL testing performed at 90° of flexion with 0.5 N·m of valgus moment preload, (2) cyclic loading from 0.5 to 5 N·m of valgus moment for 1000 cycles at 1 Hz, and (3) load to failure at 0.2 mm/s. Elbows then underwent UCL reconstruction with 1 elbow of each pair receiving the classic docking technique using either anatomic (proximal to distal) or traditional (anterior to posterior) tunnel locations. Specimen testing was then repeated as described. Results: There were no differences in maximum load at failure between the anatomic and traditional tunnel location techniques (mean ± SD, 34.90 ± 10.65 vs 37.28 ± 14.26 N·m; P = .644) or when including the native UCL (45.83 ± 17.03 N·m; P = .099). Additionally, there were no differences in valgus angle after 1000 cycles across the anatomic technique (4.58°± 1.47°), traditional technique (4.08°± 1.28°), and native UCL (4.07°± 1.99°). The anatomic group and the native UCL had similar valgus angles at failure (24.13°± 5.86° vs 20.13°± 5.70°; P = .083), while the traditional group had a higher valgus angle at failure when compared with the native UCL (24.88°± 6.18° vs 19.44°± 5.86°; P = .015). Conclusion: In this cadaveric model, UCL reconstruction with the docking technique utilizing proximal-to-distal ulnar tunnels better restored the ulnar footprint while providing valgus stability comparable with reconstruction with the docking technique using traditional anterior-to-posterior ulnar tunnel locations. These results suggest that utilization of the anatomic tunnel location in UCL reconstruction has similar biomechanical properties to the traditional method at the time of initial fixation (ie, not accounting for healing after reconstruction in vivo) while keeping the ulnar tunnels farther from the ulnar nerve. Further studies are warranted to determine if an anatomically based UCL reconstruction results in differing outcomes than traditional reconstruction techniques. Clinical Relevance: Current UCL reconstruction techniques do not accurately re-create the ulnar UCL footprint. The UCL is a dynamic constraint to valgus loads at the elbow, and a more anatomic reconstruction may afford more natural joint kinematics. This more anatomic technique performs similarly to the traditional docking technique at time zero, and the results of this study may offer a starting point for future in vivo studies.

Previously Unrecognized Source of Error in the Change in Maximum Total Point Motion to Determine Continuous Migration of Unstable Tibial Baseplates

In radiostereometric analysis (RSA), continuous migration denoted as ΔMTPM is the difference between maximum total point motion (MTPM) at 2 years relative to time zero and MTPM at 1 year relative to time zero. Continuous migration has been used to diagnose tibial baseplates as stable versus unstable when compared to a specified stability limit (i.e. value of ΔMTPM). If the same point experiences MTPM at 2 years and at 1 year (usually the case for marker-based RSA), then an implicit assumption is that the migration path between 2 years and 1 year is the same as the path between 1 year and time zero. This paper uses vector analysis to demonstrate a source of error in ΔMTPM not previously recognized and estimates the error magnitude based on the interplay of independent variables which affect the error. The two independent variables which affect the error are the angle between the two migration vectors (i.e., MTPM between time zero and 2 years and MTPM between time zero and 1 year) and the difference in magnitude of the two vectors. The relative error increased in an absolute sense as the angle between the vectors increased and decreased for larger differences in the magnitudes of the two vectors. For magnitude ratios ranging from 1.25 to 2, relative errors ranged from -21% to -3% at 10° and from -78% to -42% at 60°, respectively. Knowledge of these errors highlights a limitation in the use of ΔMTPM not previously recognized.

An Accurate Doppler Parameters Calculation Method of Geosynchronous SAR Considering Real-Time Zero-Doppler Centroid Control

The zero-Doppler centroid control in geosynchronous synthetic aperture radar (GEO SAR) is beneficial to reduce the imaging complexity (reduces range-azimuth coupling in received data), which can be realized by adjusting the radar line of sight (RLS). In order to maintain the zero-Doppler centroid throughout the whole orbit of the GEO SAR satellite, the RLS needs to be adjusted in real-time. Due to the ultra-long synthetic aperture time of GEO SAR, the RLS variation during the synthetic aperture time cannot be neglected. However, in the previous related papers, the real-time variation of RLS during the synthetic aperture time was not taken into account in the calculation of Doppler parameters, which are closely related to the RLS, resulting in inaccurate calculation of Doppler parameters. Considering this issue, an accurate Doppler model (the model of relative motion between satellite and ground target) of GEO SAR is proposed in this paper for the accurate calculation of Doppler parameters (Doppler centroid and Doppler bandwidth and other parameters). Finally, simulation experiments are designed to confirm the effectiveness and necessity of the proposed model. The results indicate that the RLS variation during the synthetic aperture time has a considerable effect on Doppler parameters performance of the GEO SAR, and refers to a more stable azimuth resolution performance (the resolution is kept near a relatively stable value at most positions of the elliptical orbit) compared with the case that does not consider the real-time zero-Doppler centroid control.

An observational clinical study of the influence of phacoemulsification on choroidal neovascular membrane activity in age related macular degeneration

Background Thousands of phacoemulsification surgeries are performed on eyes with age-related macular degeneration (AMD) complicated by choroidal neovascular membrane (CNV) in the United Kingdom each year. As populations age this number is expected to rise. Controversy over phacoemulsification’s influence on CNV activity limits the information which clinicians and these patients use to decide on surgery. This observational study aims to resolve this controversy by reporting on intravitreal injection (IVI) frequency as a pragmatic marker of CNV activity in a large cohort. Methods A cohort of eyes with AMD complicated by CNV (n = 327) that underwent cataract surgery at a single tertiary centre from 2014 to 2019 were identified. These cases were matched by interval since CNV diagnosis at a specified ‘time zero’ within the follow-up of pseudophakic eyes with AMD (n = 327). Data concerning demographics, visual acuity (VA) and intravitreal injection frequency before and after ‘time zero’/phacoemulsification were collected. Results Following ‘time zero’/phacoemulsification’ the mean reduction in annual IVI frequency was 0.6 injections/year (95% CI 0.4,0.9) and 0.4 injections/year (95% CI 0.1,0.7) in the comparison and phacoemulsification cohorts respectively. The mean VA gain 12 months after phacoemulsification in the intervention cohort was 11.3 (95% CI 9.2,13.4) early treatment of diabetic retinopathy study (ETDRS) letters, with 214 eyes (65.4%) having gained ≥5 ETDRS letters after surgery. Conclusions Phacoemulsification has no clinically significant impact on the activity of pre-existent CNV secondary to AMD. Phacoemulsification should be offered to patients with AMD and cataract that limits vision, regardless of CNV activity.

Evaluation of the Intact Anterior Talofibular and Calcaneofibular Ligaments, Injuries, and Repairs With and Without Augmentation: A Biomechanical Robotic Study

Background: Acute ankle sprains are common injuries. The anterior talofibular (ATFL) and calcaneofibular ligaments (CFL) are the most injured lateral structures. However, controversy exists on the optimal surgical treatment when the injury is both acute and severe or becomes chronic and unstable. Studies have evaluated the biomechanics of these ligaments, but no studies have robotically evaluated injury effects and surgical treatment of ATFL or ATFL and CFL injuries. Purpose: To quantitatively evaluate biomechanical effects of ATFL and CFL lesions, ATFL repair, ATFL and CFL repair, and augmentation of ATFL on ankle stability. Study Design: Controlled laboratory study. Methods: Ten nonpaired cadaveric ankles were tested using a 6 degrees of freedom robot. Each ankle underwent testing in the following states sequentially: (1) intact, (2) ATFL cut, (3) CFL cut, (4) ATFL repair + CFL cut, (5) ATFL repair + CFL repair, and (6) ATFL repair with augmentation with suture tape + CFL repair. Testing included 88 N anterior drawer and 5 N·m varus talar tilt tests at 0° and 30° of plantarflexion, and 88 N Cotton test at 0° of plantarflexion. Results: After all surgical treatments ankles still had increased laxity compared with intact state testing, except after augmented ATFL repair + CFL repair in anterior drawer testing at 30° of plantarflexion ( P = .393). Sectioning the CFL caused a significant increase in talar tilt compared with the ATFL cut state at 0° ( P < .001) and 30° of plantarflexion ( P < .001), but no increase in anterior drawer or Cotton tests. Conclusion: Complete native stability may not be attainable at time zero repair with the tested treatments. The option that best returned stability in anterior translation was augmented ATFL repair with nonaugmented CFL repair. The importance of the CFL as a primary ligamentous stabilizer for talar tilt was confirmed. Clinical Relevance: Evaluating lateral ankle stability and treatment with a 6 degrees of freedom robot should help delineate optimal treatment options. Findings in this study show that none of the repair methods at time zero restored kinematics to the intact state. Of the tested states, the augmented ATFL repair with CFL repair was the best option for controlling anterior translation at time zero. The importance of addressing the CFL to correct talar tilt instability was suggested as was the importance of a period of immobilization before beginning protected rehabilitation. The benefit of ATFL repair augmentation with suture tape is in limiting the postoperative motion in an anterior drawer motion to just 0.5 to 1 mm, but there was no significant improvement to talar tilt even with CFL repair, suggesting that further consideration should be given to CFL augmentation in future studies.