Response- and Progression-Based End Points in Trial and Observational Cohorts of Patients With NSCLC.

Importance: Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making. Objective: To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC. Exposure: All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed. Main Outcomes and Measures: End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR. Results: A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment. Conclusions and Relevance: In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.

The influence of induced gait asymmetry on joint reaction forces.

Chronic injury- or disease-induced joint impairments result in asymmetric gait deviations that may precipitate changes in joint loading associated with pain and osteoarthritis. Understanding the impact of gait deviations on joint reaction forces (JRFs) is challenging because of concurrent neurological and/or anatomical changes and because measuring JRFs requires medically invasive instrumented implants. Instead, we investigated the impact of joint motion limitations and induced asymmetry on JRFs by simulating data recorded as 8 unimpaired participants walked with bracing to unilaterally and bilaterally restrict ankle, knee, and simultaneous ankle + knee motion. Personalized models, calculated kinematics, and ground reaction forces (GRFs) were input into a computed muscle control tool to determine lower limb JRFs and simulated muscle activations guided by electromyography-driven timing constraints. Unilateral knee restriction increased GRF peak and loading rate ipsilaterally but peak values decreased contralaterally when compared to walking without joint restriction. GRF peak and loading rate increased with bilateral restriction compared to the contralateral limb of unilaterally restricted conditions. Despite changes in GRFs, JRFs were relatively unchanged due to reduced muscle forces during loading response. Thus, while joint restriction results in increased limb loading, reductions in muscle forces counteract changes in limb loading such that JRFs were relatively unchanged.

Reduced joint motion supersedes asymmetry in explaining increased metabolic demand during walking with mechanical restriction.

Recent research has highlighted the complex interactions among chronic injury- or disease-induced joint limitations, walking asymmetry, and increased metabolic cost. Determining the specific metabolic impacts of asymmetry or joint impairment in clinical populations is difficult because of concurrent neurological and physiological changes. This work investigates the metabolic impact of gait asymmetry and joint restriction by unilaterally (asymmetric) and bilaterally (symmetric) restricting ankle, knee, and combined ankle and knee ranges of motion in unimpaired individuals. We calculated propulsive asymmetry, temporal asymmetry, and step-length asymmetry for an average gait cycle; metabolic rate; average positive center of mass power using the individual limbs method; and muscle effort using lower limb electromyography measurements weighted by corresponding physiological cross-sectional areas. Unilateral restriction caused propulsive and temporal asymmetry but less metabolically expensive gait than bilateral restriction. Changes in asymmetry did not correlate with changes in metabolic cost. Interestingly, bilateral restriction increased average positive center of mass power compared to unilateral restriction. Further, increased average positive center of mass power correlated with increased energy costs, suggesting asymmetric step-to-step transitions did not drive metabolic changes. The number of restricted joints reduces available degrees of freedom and may have a larger metabolic impact than gait asymmetry, as this correlated significantly with increases in metabolic rate for 7/9 participants. These results emphasize symmetry is not by definition metabolically optimal, indicate that the mechanics underlying symmetry are meaningful, and suggest that available degrees of freedom should be considered in designing future interventions.

Isolating the energetic and mechanical consequences of imposed reductions in ankle and knee flexion during gait.

BACKGROUND: Weakness of ankle and knee musculature following injury or disorder results in reduced joint motion associated with metabolically expensive gait compensations to enable limb support and advancement. However, neuromechanical coupling between the ankle and knee make it difficult to discern independent roles of these restrictions in joint motion on compensatory mechanics and metabolic penalties. METHODS: We sought to determine relative impacts of ankle and knee impairment on compensatory gait strategies and energetic outcomes using an unimpaired cohort (N = 15) with imposed unilateral joint range of motion restrictions as a surrogate for reduced motion resulting from gait pathology. Participants walked on a dual-belt instrumented treadmill at 0.8 m s-1 using a 3D printed ankle stay and a knee brace to systematically limit ankle motion (restricted-ank), knee motion (restricted-knee), and ankle and knee motion (restricted-a + k) simultaneously. In addition, participants walked without any ankle or knee bracing (control) and with knee bracing worn but unrestricted (braced). RESULTS: When ankle motion was restricted (restricted-ank, restricted-a + k) we observed decreased peak propulsion relative to the braced condition on the restricted limb. Reduced knee motion (restricted-knee, restricted-a + k) increased restricted limb circumduction relative to the restricted-ank condition through ipsilateral hip hiking. Interestingly, restricted limb average positive hip power increased in the restricted-ank condition but decreased in the restricted-a + k and restricted-knee conditions, suggesting that locking the knee impeded hip compensation. As expected, reduced ankle motion, either without (restricted-ank) or in addition to knee restriction (restricted-a + k) yielded significant increase in net metabolic rate when compared with the braced condition. Furthermore, the relative increase in metabolic cost was significantly larger with restricted-a + k when compared to restricted-knee condition. CONCLUSIONS: Our methods allowed for the reproduction of asymmetric gait characteristics including reduced propulsive symmetry and increased circumduction. The metabolic consequences bolster the potential energetic benefit of targeting ankle function during rehabilitation. TRIAL REGISTRATION: N/A.

Mechanics and energetics of post-stroke walking aided by a powered ankle exoskeleton with speed-adaptive myoelectric control.

BACKGROUND: Ankle exoskeletons offer a promising opportunity to offset mechanical deficits after stroke by applying the needed torque at the paretic ankle. Because joint torque is related to gait speed, it is important to consider the user's gait speed when determining the magnitude of assistive joint torque. We developed and tested a novel exoskeleton controller for delivering propulsive assistance which modulates exoskeleton torque magnitude based on both soleus muscle activity and walking speed. The purpose of this research is to assess the impact of the resulting exoskeleton assistance on post-stroke walking performance across a range of walking speeds. METHODS: Six participants with stroke walked with and without assistance applied to a powered ankle exoskeleton on the paretic limb. Walking speed started at 60% of their comfortable overground speed and was increased each minute (n00, n01, n02, etc.). We measured lower limb joint and limb powers, metabolic cost of transport, paretic and non-paretic limb propulsion, and trailing limb angle. RESULTS: Exoskeleton assistance increased with walking speed, verifying the speed-adaptive nature of the controller. Both paretic ankle joint power and total limb power increased significantly with exoskeleton assistance at six walking speeds (n00, n01, n02, n03, n04, n05). Despite these joint- and limb-level benefits associated with exoskeleton assistance, no subject averaged metabolic benefits were evident when compared to the unassisted condition. Both paretic trailing limb angle and integrated anterior paretic ground reaction forces were reduced with assistance applied as compared to no assistance at four speeds (n00, n01, n02, n03). CONCLUSIONS: Our results suggest that despite appropriate scaling of ankle assistance by the exoskeleton controller, suboptimal limb posture limited the conversion of exoskeleton assistance into forward propulsion. Future studies could include biofeedback or verbal cues to guide users into limb configurations that encourage the conversion of mechanical power at the ankle to forward propulsion. TRIAL REGISTRATION: N/A.

Spatial Dependency of Glenohumeral Joint Stability During Dynamic Unimanual and Bimanual Pushing and Pulling.

Degenerative wear to the glenoid from repetitive loading can reduce effective concavity depth and lead to future instability. Workspace design should consider glenohumeral stability to prevent initial wear. While glenohumeral stability has been previously explored for activities of daily living including push-pull tasks, whether stability is spatially dependent is unexplored. We simulated bimanual and unimanual push-pull tasks to four horizontal targets (planes of elevation: 0 deg, 45 deg, 90 deg, and 135 deg) at 90 deg thoracohumeral elevation and three elevation targets (thoracohumeral elevations: 20 deg, 90 deg, 170 deg) at 90 deg plane of elevation. The 45 deg horizontal target was most stable regardless of exertion type and would be the ideal target placement when considering stability. This target is likely more stable because the applied load acts perpendicular to the glenoid, limiting shear force production. The 135 deg horizontal target was particularly unstable for unimanual pushing (143% less stable than the 45 deg target), and the applied force for this task acts parallel to the glenoid, likely creating shear forces or limiting compressive forces. Pushing was less stable than pulling (all targets except sagittal 170 deg for both task types and horizontal 45 deg for bimanual) (p < 0.01), which is consistent with prior reports. For example, unimanual pushing at the 90 deg horizontal target was 197% less stable than unimanual pulling. There were limited stability benefits to task placement for pushing, and larger stability benefits may be seen from converting tasks from push to pull rather than optimizing task layout. There was no difference in stability between bimanual and unimanual tasks, suggesting no stability benefit to bimanual operation.

Spatial dependency of shoulder muscle demand during dynamic unimanual and bimanual pushing and pulling.

Work involving extensive pushing and pulling is associated with higher frequency of shoulder complaints. While reports of shoulder muscle demand during submaximal isometric tasks are abundant, dynamic submaximal push-pull exertions are not well understood. We evaluated how muscle demand (weighted EMG average) of surface glenohumeral muscles varies with task type and target. Seventeen healthy young adults performed seated unimanual and bimanual pushes and pulls to 3 thoracohumeral elevations (20°, 90°, 170°) and 4 elevation planes (0°, 45°, 90°, 135°) with loading at 15% of isometric push-pull capacity. Pulling required less demand than pushing (p < 0.0001). Muscle demand varied more with elevation than elevation plane. The lowest target had highest demand for pulling (p < 0.01), and the most elevated target had highest demand for pushing (p < 0.0001). Working above the shoulder is known to increase demand during isometric tasks, however, these results suggest that for dynamic tasks working against gravity has a larger effect on demand than task target.