Achieving Specified Laxity in a Noncruciate Total Knee: A Laboratory Design Study.

BACKGROUND: Noncruciate total knee arthroplasty designs, including ultracongruent, medially congruent, and medial pivot, are gaining increasing attention in total knee arthroplasty surgery. However, there is no consensus for the bearing surface design, whether there should be different medial, lateral, anterior, and posterior laxities, or whether the medial side should be a medial pivot. This study proposes the criterion of reproducing the laxity of the anatomic knee, defined as the displacements and rotations of the femur on the tibia in the loaded knee when shear and torque are applied. The purpose of this study was to determine the ideal tibial radii to achieve that goal. METHODS: The femoral component was based on the average knee from 100 mild arthritic knee scans. There were 8 tibial components that were designed with different sagittal radii: antero-medial, antero-lateral, postero-medial, and postero-lateral. Radii were defined as the percent height reduction from full conformity with the femoral profile. Components were 3-dimensional-printed. A test rig was constructed where the tibial component was fixed and shear and torque were applied to the femoral component. Displacements and rotations of the femoral component were measured at 0 and 45° of flexion, the latter representing any flexion angle due to the constant femoral sagittal radius. RESULTS: Displacements ranged from 0 to 11 mm, and rotations ranged from 1 to 11°. Anterior femoral displacements were higher than posterior due to the shallow distal-anterior femoral profile. The final femoral and tibial components with the most closely matched anatomic laxity values were designed and tested. CONCLUSIONS: A steeper distal-anterior femoral radius was an advantage. High medial-anterior tibial conformity was important. However, on the lateral side, the posterior sagittal tibial radius had to be shallower than ideal to allow femoral rollback in high flexion. This meant that the posterior laxity displacements on the lateral side were higher than anatomic, and there was no guidance for lateral femoral rollback.

Design and evaluation of a 3D printed mechanical balancer for soft tissue balancing in total knee replacement.

PURPOSE: Soft tissue balancing is an important step in a total knee procedure, carried out manually, or using an indicator. The purpose of this study was to evaluate our design of 3D printed Balancer, and demonstrate how it could be used at surgery. PROCEDURES: When inserted between the femur and tibia, the Balancer displayed the forces acting across the lateral and medial compartments, indicated by pointers at the end of the handle. A loading rig was used to measure the pointer deflections for different forces applied at different locations on the condyle surfaces. Repeatability and reproducibilty were evaluated. The Balancer was tested in six fresh knee specimens using a surgical simulation rig. MAIN FINDINGS: Pointer deflections of up to 12 millimeters occurred for less than 1 mm displacements at the condyle surfaces. Reproducibility tests showed a standard deviation of 14% at lower loads, reducing to only 4% at higher loads. Mean pointer deflections were within 8% for forces applied at ±10 mm AP, and +5/-3 mm in an ML direction, relative to the neutral contact point. In specimens, most lateral to medial force differences could be corrected by a 2° change in frontal plane angle of the tibial resection. Effects of ligament releases were also demonstrated. PRINCIPAL CONCLUSIONS: The 3D printed Balancer was easy to use, and provided the surgeon with lateral and medial force data over a full range of flexion, enabling possible corrective procedures to be specified.

The effect of total knee geometries on kinematics: An experimental study using a crouching machine.

Obtaining anatomic knee kinematics after a total knee is likely to improve outcomes. We used a crouching machine to compare the kinematics of standard condylar designs with guided motion designs. The standard condylars included femoral sagittal radii with constant radius, J-curve and G-curve; the tibial surfaces were of low and high constraint. The guided motion designs were a medial pivot and a design with asymmetric condylar shapes and guiding surfaces. The machine had a flexion range from 0° to 125°, applied quadriceps and hamstring loading, and simulated the collateral soft tissues. The kinematics of all standard condylar knees were similar, showing only small anterior-posterior displacements and internal-external rotations. The two asymmetric designs showed posterior displacements during flexion, but less axial rotations than anatomic knees. The quadriceps forces throughout flexion were very similar between all designs, reflecting similar lever arms. It was concluded that standard condylar designs, even with variations in sagittal radii, are unlikely to reproduce anatomic kinematics. On the other hand, designs with asymmetric constraint between medial and lateral sides, and other guiding features, are likely to be the way forward. The mechanical testing method could be further improved by superimposing shear forces and torques during the flexion-extension motion, to include more stressful in vivo functional conditions.

Immune-related adverse events with PD-1 versus PD-L1 inhibitors: a meta-analysis of 8730 patients from clinical trials.

Background: Trial-level meta-analysis to investigate differences in immune-related adverse event (irAE) profiles between anti-PD-1/PD-L1 antibodies. Materials & methods: Data analyzed from 8730 patients treated with anti-PD-1/PD-L1 monotherapy. Incidence and odds ratios (ORs) were calculated for irAEs overall, selected individual irAEs for individual agents and pooled estimates for anti-PD-1 or anti-PD-L1 antibodies. Results: For anti-PD-L1 versus anti-PD-1 antibodies, we observed a lower risk of any-grade rash, elevated alanine aminotransferase, colitis, grade ≥3 colitis, hypothyroidism and rash. For individual agents, we observed reduced risks of overall any-grade irAEs for atezolizumab versus pembrolizumab and grade ≥3 irAEs for avelumab versus pembrolizumab. Conclusion: irAE risk may vary between anti-PD-1 and anti-PD-L1 antibodies; however, findings are hypothesis-generating.

Five-Factor Prognostic Model for Survival of Post-Platinum Patients with Metastatic Urothelial Carcinoma Receiving PD-L1 Inhibitors.

PURPOSE: A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting. MATERIALS AND METHODS: Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets. RESULTS: The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.

Biomechanical Implications of an Oblique Knee Joint Line.

Surgical correction of multiapical deformities of the lower limb requires careful preoperative planning. Surgeons must account for the potential creation of secondary deformity, such as knee joint line obliquity, and the risks associated with accepting these changes in limb alignment. In this study, we evaluate the effect of knee joint obliquity on tibial plateau contact pressures and knee instability. Three cadaveric knees were dissected and put through biomechanical testing to simulate loading of an oblique knee joint. We observed < 1 mm femoral displacement (proxy measure of instability) between 15 degrees of varus tilt and 10 degrees of valgus tilt, and greater increases in tibial plateau contact pressures with valgus tilt than with varus tilt. Our results suggest that, if the creation of a secondary coronal plane deformity at the knee joint cannot be avoided, up to 15 degrees of varus or 10 degrees of valgus alignment can be tolerated by an otherwise structurally normal knee.

Sequencing of Cabazitaxel and Abiraterone Acetate After Docetaxel in Metastatic Castration-Resistant Prostate Cancer: Treatment Patterns and Clinical Outcomes in Multicenter Community-Based US Oncology Practices.

BACKGROUND: Optimal sequencing of cabazitaxel (C) and abiraterone acetate (A) after docetaxel (D) for metastatic castration-resistant prostate cancer (mCRPC) is unclear. We assessed treatment patterns and outcomes in patients with mCRPC receiving different sequences of A or C, or both, after administration of D. METHODS: Retrospective analysis was conducted of US Oncology Network iKnowMed (iKM) electronic health record (EHR) data to assess patients with mCRPC who received treatment with D and were subsequently treated with C or A, or both, between April 2011 and May 2012. Patients received 2 or 3 drugs: DA, DC, DAC, or DCA. Overall survival (OS) and time to treatment failure (TTF) were analyzed by the Kaplan-Meier method from the start to the end of second-line therapy after administration of D (TTF1) and to the end of combined second- and third-line therapy (TTF2) for 3-drug sequences. Multivariable Cox proportional hazard models evaluated the impact of baseline clinical prognostic factors and treatment sequence on OS and TTF. RESULTS: Of 350 patients who were treated with D and subsequent therapies, 183 (52.3%) received DA, 54 (15.4%) received DC, 77 (22.0%) received DCA, and 36 (10.3%) received DAC. In a multivariable analysis, adjusted comparisons suggested that 3-drug sequences were associated with improved OS versus 2-drug sequences (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.092-0.476; P = .0002). There were no statistically significant differences in OS and TTF for DC versus DA, and OS was significantly greater for DCA versus DAC (HR, 0.13; 95% CI, 0.022-0.733; P = .0210). More cycles of C were administered in DCA than in DAC (median 6 vs. 4; t test P < .0001), whereas the duration of A treatment was similar. CONCLUSION: Administration of 3 agents in the DCA sequence was more optimal for treating mCRPC in this hypothesis-generating study.

Treatment patterns and clinical effectiveness in metastatic castrate resistant prostate cancer after first-line docetaxel.

BACKGROUND: Treatment for metastatic castrate-resistant prostate cancer in community settings is not well understood. OBJECTIVE: To examine treatment patterns, sequencing, and outcomes in patients receiving second- and third-line treatment after first-line docetaxel. METHODS: We used a community oncology database to identify patients who progressed after line 1 docetaxel (D) and received line 2 cabazitaxel (DC), abiraterone (DA), or other therapy (DO). Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan- Meier and Cox regression models. Line 3 included subsets DCA and DAC. RESULTS: Line 2 groups (DC = 60 patients, DA = 71, DO = 153) did not differ significantly on demographic and clinical characteristics or median PFS on docetaxel therapy. Cox regression for OS by line 2 groups showed increased risk for DA compared with DC (HR, 1.69; P = .026) when 24 untreated DO patients were excluded. A similar nonsignificant pattern was observed when the 24 untreated patients were included. Of patients receiving DC in line 2, a nominally greater proportion received A in line 3 (57%, 34 of 60 patients) than did patients who received DA in line 2 followed by C in line 3 (25%, 18 of 71). LIMITATIONS: There was a small sample for line 3, and unexamined confounds and selection biases in observational research. Conclusions Treatment patterns in community settings following docetaxel are complex and may involve multiple hormonal agents prior to disease progression. Cabazitaxel may not be optimally used in advanced disease. Although Cox regression showed increased risk of death for DA compared with DC, results need to be validated prospectively. CONCLUSIONS: Treatment patterns in community settings following docetaxel are complex and may involve multiple hormonal agents prior to disease progression. Cabazitaxel may not be optimally used in advanced disease. Although Cox regression showed increased risk of death for DA compared with DC, results need to be validated prospectively.

Acute toxicity of cadmium, lead, zinc, and their mixtures to stream-resident fish and invertebrates.

The authors conducted 150 tests of the acute toxicity of resident fish and invertebrates to Cd, Pb, and Zn, separately and in mixtures, in waters from the South Fork Coeur d'Alene River watershed, Idaho, USA. Field-collected shorthead sculpin (Cottus confusus), westslope cutthroat trout (Oncorhynchus clarkii lewisi), two mayflies (Baetis tricaudatus and Rhithrogena sp.), a stonefly (Sweltsa sp.), a caddisfly (Arctopsyche sp.), a snail (Gyraulus sp.), and hatchery rainbow trout (Oncorhynchus mykiss), were tested with all three metals. With Pb, the mayflies (Drunella sp., Epeorus sp., and Leptophlebiidae), a Simuliidae black fly, a Chironomidae midge, a Tipula sp. crane fly, a Dytiscidae beetle, and another snail (Physa sp.), were also tested. Adult westslope cutthroat trout were captured to establish a broodstock to provide fry of known ages for testing. With Cd, the range of 96-h median effect concentrations (EC50s) was 0.4 to >5,329 µg/L, and the relative resistances of taxa were westslope cutthroat trout ≈ rainbow trout ≈ sculpin << other taxa; with Pb, EC50s ranged from 47 to 3,323 µg/L, with westslope cutthroat trout < rainbow trout < other taxa; and with Zn, EC50s ranged from 21 to 3,704 µg/L, with rainbow trout < westslope cutthroat trout ≈ sculpin << other taxa. With swim-up trout fry, a pattern of decreasing resistance with increasing fish size was observed. In metal mixtures, the toxicities of the three metals were less than additive on a concentration-addition basis.

Epitaxial oxide bilayer on Pt (001) nanofacets.

We observed an epitaxial, air-stable, partially registered (2 × 1) oxide bilayer on Pt (001) nanofacets [V. Komanicky, A. Menzel, K.-C. Chang, and H. You, J. Phys. Chem. 109, 23543 (2005)]. The bilayer is made of two half Pt layers; the top layer has four oxygen bonds and the second layer two. The positions and oxidation states of the Pt atoms are determined by analyzing crystal truncation rods and resonance scattering data. The positions of oxygen atoms are determined by density functional theory (DFT) calculations. Partial registry on the nanofacets and the absence of such registry on the extended Pt (001) surface prepared similarly are explained in DFT calculations by strain relief that can be accommodated only by nanoscale facets.

Automatic implementation of precise grid screens: the four-corners method.

Crystallization trials can be designed as a systematic gradient of the concentration of key reagents and/or pH centered on the original conditions. While the concept of the grid screen is simple, its implementation is tedious and difficult by hand. A procedure has been developed for preparing crystallization grid screens that is both efficient and achieves high accuracy because it relies on a limited number of solutions that are carefully prepared by hand. The ;four-corners' approach to designing grid screens uses the minimum and maximum concentrations of the components being varied in the grid screen as the sole stock solutions. For an N-dimensional grid only 2(N) corner solutions require detailed preparation, making the screens efficient. Furthermore, by keeping the concentrations as tight as possible to the grid, the potential impact of pipette errors is minimized, creating a highly precise screen.

Shape-dependent activity of platinum array catalyst.

We produced millions of morphologically identical platinum catalyst nanoparticles in the form of ordered arrays epitaxially grown on (111), (100), and (110) strontium titanate substrates using electron beam lithography. The ability to design, produce, and characterize the catalyst nanoparticles allowed us to relate microscopic morphologies with macroscopic catalytic reactivities. We evaluated the activity of three different arrays containing different ratios of (111) and (100) facets for an oxygen-reduction reaction, the most important reaction for fuel cells. Increased catalytic activity of the arrays points to a possible cooperative interplay between facets with different affinities to oxygen. We suggest that the surface area of (100) facets is one of the key factors governing catalyst performance in the electrochemical reduction of oxygen molecules.

Machine-learning techniques for macromolecular crystallization data.

Systematizing belief systems regarding macromolecular crystallization has two major advantages: automation and clarification. In this paper, methodologies are presented for systematizing and representing knowledge about the chemical and physical properties of additives used in crystallization experiments. A novel autonomous discovery program is introduced as a method to prune rule-based models produced from crystallization data augmented with such knowledge. Computational experiments indicate that such a system can retain and present informative rules pertaining to protein crystallization that warrant further confirmation via experimental techniques.

Anemia in stage II and III breast cancer patients treated with adjuvant doxorubicin and cyclophosphamide chemotherapy.

PURPOSE: The incidence and severity of prechemotherapy anemia and chemotherapy-induced anemia experienced by women treated with adjuvant doxorubicin and cyclophosphamide (AC) therapy for stage II and III breast cancer are described. PATIENTS AND METHODS: Medical charts of 310 breast cancer patients who received chemotherapy at eight oncology practices during 1997 through 2001 were reviewed in this historical case series study. Prechemotherapy anemia was defined as a baseline hemoglobin value <12 g/dl. An anemic event during chemotherapy (used to define chemotherapy-induced anemia) was defined as either a drop in hemoglobin level below the threshold (< or = 10 g/dl), the receipt of a blood transfusion(s), or treatment with epoetin alfa. RESULTS: Overall, 40.0% of patients experienced moderate to severe anemia (i.e., their hemoglobin levels dropped to <10 g/dl) and 31.3% (97/310) were anemic prechemotherapy. Of the patients with mild anemia prechemotherapy, 61.9% developed moderate to severe anemia during chemotherapy. Only 47.4% (46/97) of those patients received epoetin alfa therapy during chemotherapy. Of the patients with normal prechemotherapy hemoglobin levels (> or = 12 g/dl), 88.3% developed some degree of anemia (<12 g/dl) during chemotherapy and 27.7% (59/213) developed moderate to severe anemia (<10 g/dl). Anemic events were experienced by 41.8% (89/213) of the patients with normal prechemotherapy hemoglobin levels. CONCLUSIONS: We conclude that a significant proportion (31.3%) of stage II and III breast cancer patients are anemic prechemotherapy and that the incidence of anemia increases substantially from prechemotherapy through the postchemotherapy period. This evidence appears to warrant earlier evaluation of anemia and an intervention in the prechemotherapy stage.

Recovery of phenytoin from feeding formulas and protein mixtures.

The recovery of phenytoin from mixtures containing different phenytoin formulations and protein mixtures was studied. Three phenytoin solutions (40 mg/microL) were prepared, each in triplicate, from phenytoin tablets, phenytoin suspension, and bulk phenytoin powder. These solutions were mixed with equivalent volumes of two commercially available feeding formulas (Replete and Ultracal) and two isolated protein mixtures (casein protein mixture and why protein isolates mixture) and placed in ultrafiltration tubes. The mixtures were centrifuged, and phenytoin recovery was determined by using high-performance liquid chromatography. Control data were also obtained before and after the experiment. There was no difference in phenytoin recovery when comparing phenytoin tablets versus phenytoin suspension in any of the protein media. There was a significant difference in phenytoin recovery when comparing the standard phenytoin solution mixed with Replete (32.51%) versus Ultracal (37.71%). There was also a significant difference in recovery when comparing the standard solution mixed with the calcium caseinate mixture (48.41%) versus the whey protein isolates mixture (82.01%). While the difference in recovery between Replete and Ultracal was expected, the significantly higher recovery of phenytoin from the whey protein mixture versus the calcium caseinate mixture indicated a much lower binding affinity between phenytoin and whey protein than with phenytoin and casein. The recovery of unbound phenytoin from feeding formulas and solutions of protein isolates did not differ with phenytoin formulations. Ultracal had a lower level of binding to phenytoin than Replete; whey protein had a lower level of binding than casein.