Older adults use fewer muscles to overcome perturbations during a seated locomotor task.

Locomotor perturbations provide insights into humans' response to motor errors. We investigated the differences in motor adaptation and muscle cocontraction between young and older adults during perturbed-arm and -leg recumbent stepping. We hypothesized that besides prolonged adaptation due to use-dependent learning, older adults would exhibit greater muscle cocontraction than young adults in response to the perturbations. Perturbations were brief increases in resistance applied during each stride at the extension onset or midextension of the left or right leg. Seventeen young adults and eleven older adults completed four 10-min perturbed stepping tasks. Subjects were instructed to follow a visual pacing cue, step smoothly, and use all their limbs to drive the stepper. Results showed that young and older adults did not decrease their errors with more perturbation experience, and errors did not wash out after perturbations were removed. Interestingly, older adults consistently had smaller motor errors than young adults in response to the perturbations. Older adults used fewer muscles to drive the stepper and had greater cocontraction than young adults. The results suggest that, despite similar motor error responses, young and older adults use distinctive muscle recruitment patterns to perform the motor task. Age-related motor strategies help track motor changes across the human life span and are a baseline for rehabilitation and performance assessment.NEW & NOTEWORTHY Older adults often demonstrate greater cocontraction and motor errors than young adults in response to motor perturbations. We demonstrated that older adults reduced their motor errors more than young adults with brief perturbations during recumbent stepping while maintaining greater muscle cocontraction. In doing so, older adults largely used one muscle pair to drive the stepper, tibialis anterior and soleus, whereas young adults used all muscles. These two muscles are crucial for maintaining upright balance.

Mutation-Agnostic Detection of Colorectal Cancer Using Liquid Biopsy-Based Methylation-Specific Signatures.

Detection of methylation patterns in circulating tumor DNA (ctDNA) can offer a novel approach for cancer diagnostics given the unique signature for each tumor type. We developed a next-generation sequencing (NGS)-based assay targeting 32 CpG sites to detect colorectal cancer-specific ctDNA. NGS was performed on bisulfite-converted libraries and status dichotomization was done using median methylation ratios at all targets. We included plasma samples from patients with metastatic colorectal (n = 20) and non-colorectal cancers (n = 8); and healthy volunteers (n = 4). Median methylation ratio was higher in colorectal cancer compared with non-colorectal cancers (P = .001) and normal donors (P = .005). The assay detected ctDNA in 85% of patients with colorectal cancer at a specificity of 92%. Notably, we were able to detect methylated ctDNA in 75% of patients in whom ctDNA was not detected by other methods. Detection of methylated ctDNA was associated with shorter median progression-free survival compared to non-detection (8 weeks versus 54 weeks; P = .027).

Racial disparities in EEG research and their implications for our understanding of the maternal brain.

Racial disparities in maternal health are alarming and persistent. Use of electroencephalography (EEG) and event-related potentials (ERPs) to understand the maternal brain can improve our knowledge of maternal health by providing insight into mechanisms underlying maternal well-being, including implications for child development. However, systematic racial bias exists in EEG methodology-particularly for Black individuals-and in psychological and health research broadly. This paper discusses these biases in the context of EEG/ERP research on the maternal brain. First, we assess the racial/ethnic diversity of existing ERP studies of maternal neural responding to infant/child emotional expressions, using papers from a recent meta-analysis, finding that the majority of mothers represented in this research are of White/European ancestry and that the racially and ethnically diverse samples that are present are limited in terms of geography. Therefore, our current knowledge base in this area may be biased and not generalizable across racially diverse mothers. We outline factors underlying this problem, beginning with the racial bias in EEG equipment that systematically excludes individuals of African descent, and also considering factors specific to research with mothers. Finally, we highlight recent innovations to EEG hardware to better accommodate diverse hairstyles and textures, and other important steps to increase racial and ethnic representativeness in EEG/ERP research with mothers. We urge EEG/ERP researchers who study the maternal brain-including our own research group-to take action to increase racial diversity so that this research area can confidently inform understanding of maternal health and contribute to minimizing maternal health disparities.

Small directional treadmill perturbations induce differential gait stability adaptation.

Introducing unexpected perturbations to challenge gait stability is an effective approach to investigate balance control strategies. Little is known about the extent to which people can respond to small perturbations during walking. This study aimed to determine how subjects adapted gait stability to multidirectional perturbations with small magnitudes applied on a stride-by-stride basis. Ten healthy young subjects walked on a treadmill that either briefly decelerated belt speed ("stick"), accelerated belt speed ("slip"), or shifted the platform medial-laterally at right leg mid-stance. We quantified gait stability adaptation in both anterior-posterior and medial-lateral directions using margin of stability and its components, base of support, and extrapolated center of mass. Gait stability was disrupted upon initially experiencing the small perturbations as margin of stability decreased in the stick, slip, and medial shift perturbations and increased in the lateral shift perturbation. Gait stability metrics were generally disrupted more for perturbations in the coincident direction. Subjects employed both feedback and feedforward strategies in response to the small perturbations, but mostly used feedback strategies during adaptation. Subjects primarily used base of support (foot placement) control in the lateral shift perturbation and extrapolated center of mass control in the slip and medial shift perturbations. These findings provide new knowledge about the extent of gait stability adaptation to small magnitude perturbations applied on a stride-by-stride basis and reveal potential new approaches for balance training interventions to target foot placement and center of mass control.NEW & NOTEWORTHY Little is known about if and how humans can adapt to small magnitude perturbations experienced on a stride-by-stride basis during walking. Here, we show that even small perturbations disrupted gait stability and that subjects could still adapt their reactive balance control. Depending on the perturbation direction, subjects might prefer adjusting their foot placement over their center of mass and vice versa. These findings could help potentially tune balance training to target specific aspects of balance.

Dose-escalation study of vemurafenib with sorafenib or crizotinib in patients with BRAF-mutated advanced cancers.

BACKGROUND: BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance. METHODS: Patients with advanced cancers and BRAF mutations were enrolled in a dose-escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC). RESULTS: In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am/200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF-mutant DNA from plasma during therapy (P = .005). CONCLUSIONS: Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors.

Dry Epidermal Electrodes Can Provide Long-Term High Fidelity Electromyography for Limited Dynamic Lower Limb Movements.

Due to the limitations of standard wet Silver/Silver Chloride (Ag/AgCl) hydrogel electrodes and the growing demand for long-term high fidelity surface electromyography (EMG) recording, dry epidermal electrodes are of great interest. Evaluating the usability and signal fidelity of dry epidermal electrodes could help determine the extent of potential applications using EMG electrodes. We collected EMG signals over eight days from the right rectus femoris of seven subjects using single-use dry epidermal electrodes and traditional Ag/AgCl electrodes while covered and uncovered during dynamic movements (leg extension, sit-to-stand, and treadmill walking at 0.75 m/s and 1.30 m/s). We quantified signal fidelity using signal-to-noise ratio (SNR); signal-to-motion ratio (SMR); and a metric we previously developed, the Signal Quality Index, which considers that better EMG signal quality requires both good signal-to-noise ratio and good signal-to-motion ratio. Wear patterns over the eight days degraded EMG signal quality. Uncovered epidermal electrodes that remained intact and maintained good adhesion to the skin had signal-to-noise ratios, signal-to-motion ratios, and Signal Quality Index values that were above the acceptable thresholds for limited dynamic lower limb movements (leg extension and sit-to-stand). This indicated that dry epidermal electrodes could provide good signal quality across all subjects for five days for these movements. For walking, the signal-to-noise ratios of the uncovered epidermal electrodes were still above the acceptable threshold, but signal-to-motion ratios and the Signal Quality Index values were far below the acceptable thresholds. The signal quality of the epidermal electrodes that showed no visible wear was stable over five days. As expected, covering the epidermal electrodes improved signal quality, but only for limited dynamic lower limb movements. Overall, single-use dry epidermal electrodes were able to maintain high signal quality for long-term EMG recording during limited dynamic lower limb movements, but further improvement is needed to reduce motion artifacts for whole body dynamic movements such as walking.

Assessing Fall Risk Appraisal Through Combined Physiological and Perceived Fall Risk Measures Using Innovative Technology.

The current study aimed to categorize fall risk appraisal and quantify discrepancies between perceived fall risk measured subjectively using the short Fall Efficacy Scale-International and physiological fall risk measured objectively using the portable BTrackS™ Assess Balance System. One hundred two community-dwelling older adults were evaluated in this cross-sectional study. Approximately 40% of participants had maladaptive fall risk appraisals, which were either irrational (high perceived risk despite low physiological fall risk) or incongruent (low perceived risk but high physiological fall risk). The remaining 60% of participants had adaptive fall risk appraisals, which were either rational (low perceived risk aligned with low physiological fall risk) or congruent (high perceived risk aligned with high physiological fall risk). Among participants with rational, congruent, irrational, and incongruent appraisals, 21.7%, 66.7%, 28%, and 18.8%, respectively, reported having a history of falls (p < 0.01). Using technology to identify discrepancies in perceived and physiological fall risks can potentially increase the success of fall risk screening and guide fall interventions to target perceived or physiological components of balance. [Journal of Gerontological Nursing, 46(4), 41-47.].

Shifting Maladaptive Fall Risk Appraisal in Older Adults through an in-Home Physio-fEedback and Exercise pRogram (PEER): A Pilot Study.

OBJECTIVES: 1) examine the preliminary effectiveness of the Physio-feEdback and Exercise pRogram (PEER) for shifting maladaptive to adaptive fall risk appraisal and reducing fall risk, 2) determine the participants' feedback and acceptability of the program. METHODS: Forty-one older adults were assigned to either PEER intervention or attention control group. The 8-week PEER intervention consists of a visual physio-feedback, cognitive reframing, and combined group and home-based exercise led by a trained peer coach. The attention control group read fall prevention brochures and continued their normal activities. BTrackS Balance Test (BBT), short version of Fall Efficacy Scale International (short FES-I) and CDC fall risk checklist were measured from pre- to post-intervention. The feedback and acceptability were conducted at the program conclusion. RESULTS: About 11% of participants in the PEER group had positive shifting but none in the attention control group. Up to 32% of the participants in attention control had negative shifting compared to 5.3% in the PEER group. PEER group reported significant decreases in fall risk and high acceptability of the program. CONCLUSIONS: PEER intervention facilitates a shift from maladaptive to adaptive fall risk appraisal and reduces fall risk. CLINICAL IMPLICATIONS: Preventive interventions promoting alignment between perceive and physiological fall risk may contribute to reducing falls and increasing exercise adherence.

Phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated melanoma and other advanced malignancies.

BACKGROUND: BRAF inhibitors are effective against selected BRAFV600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity. METHODS: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). RESULTS: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non-dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P = .045). CONCLUSIONS: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAFV600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.

Comprehensive Genomic Profiling of Hodgkin Lymphoma Reveals Recurrently Mutated Genes and Increased Mutation Burden.

BACKGROUND: The genomic landscape of Hodgkin lymphoma (HL) has been difficult to characterize due to the paucity of neoplastic cells and an abundant microenvironment. Such characterization is needed in order to improve treatment strategies. MATERIALS AND METHODS: We performed comprehensive genomic profiling (CGP) using targeted next-generation sequencing on archival formalin-fixed paraffin embedded tumor samples from 63 patients to analyze the landscape of HL. RESULTS: CGP was successful for 49/63 archival specimens (78%), and revealed aberrations impacting genes including B2M, TP53, and XPO1 (E571). Of the 34 patients for whom total mutation burden (TMB; mutations/megabase [Mb]) was assessed, 5 (15%) had high TMB (≥20 mutations/Mb), 18 (53%) had intermediate TMB (6-19 mutations/Mb), and 11 (32%) had low TMB (≤5 mutations/Mb). We next tested 13 patients' plasma cell-free DNA with droplet digital polymerase chain reaction for the presence of XPO1 E571 mutation, which was confirmed in the plasma of 31% of patients. In three patients with serially collected plasma samples, XPO1 E571K allelic frequency changes corresponded with changes in tumor size on conventional radiographic imaging. CONCLUSION: The study demonstrates that comprehensive genomic profiling of archival Hodgkin lymphoma tumor samples is feasible and leads to the identification of genes that are recurrently mutated and that Hodgkin lymphoma has increased mutation burden in the majority of samples analyzed. Furthermore, tracking of XPO1 E571 mutant allele frequency in a subset of patients may also represent a potential disease-monitoring strategy and warrants further investigation. IMPLICATIONS FOR PRACTICE: This study provides the first evidence that comprehensive genomic profiling can be performed to map the genomic landscape of Hodgkin lymphoma and that a subpopulation of patients has mutations in TP53, B2M, XPO1, and other genes. It was found that 15% of patients have high mutation burden, which, in cancers such as melanoma, may indicate sensitivity to immune checkpoint inhibitors, and may thus be explored for Hodgkin lymphoma. Lastly, this work demonstrates that changes in the mutant allele frequency of XPO1 in serially collected plasma cell-free DNA samples correspond with treatment outcomes measured with conventional radiographic imaging.

Detection of breast cancer stem cell gene mutations in circulating free DNA during the evolution of metastases.

PURPOSE: Limited knowledge exists on the detection of breast cancer stem cell (BCSC)-related mutations in circulating free DNA (cfDNA) from patients with advanced cancers. Identification of new cancer biomarkers may allow for earlier detection of disease progression and treatment strategy modifications. METHODS: We conducted a prospective study to determine the feasibility and prognostic utility of droplet digital polymerase chain reaction (ddPCR)-based BCSC gene mutation analysis of cfDNA in patients with breast cancer. RESULTS: Detection of quantitative BCSC gene mutation in cfDNA by ddPCR mirrors disease progression and thus may represent a valuable and cost-effective measure of tumor burden. We have previously shown that hematological and neurological expressed 1-like (HN1L), ribosomal protein L39 (RPL39), and myeloid leukemia factor 2 (MLF2) are novel targets for BCSC self-renewal, and targeting these genetic alterations could be useful for personalized genomic-based therapy. CONCLUSION: BCSC mutation detection in cfDNA may have important implications for diagnosis, prognosis, and serial monitoring.

Older adults learn less, but still reduce metabolic cost, during motor adaptation.

The ability to learn new movements and dynamics is important for maintaining independence with advancing age. Age-related sensorimotor changes and increased muscle coactivation likely alter the trial-and-error-based process of adapting to new movement demands (motor adaptation). Here, we asked, to what extent is motor adaptation to novel dynamics maintained in older adults (≥65 yr)? We hypothesized that older adults would adapt to the novel dynamics less well than young adults. Because older adults often use muscle coactivation, we expected older adults to use greater muscle coactivation during motor adaptation than young adults. Nevertheless, we predicted that older adults would reduce muscle activity and metabolic cost with motor adaptation, similar to young adults. Seated older (n = 11, 73.8 ± 5.6 yr) and young (n = 15, 23.8 ± 4.7 yr) adults made targeted reaching movements while grasping a robotic arm. We measured their metabolic rate continuously via expired gas analysis. A force field was used to add novel dynamics. Older adults had greater movement deviations and compensated for just 65% of the novel dynamics compared with 84% in young adults. As expected, older adults used greater muscle coactivation than young adults. Last, older adults reduced muscle activity with motor adaptation and had consistent reductions in metabolic cost later during motor adaptation, similar to young adults. These results suggest that despite increased muscle coactivation, older adults can adapt to the novel dynamics, albeit less accurately. These results also suggest that reductions in metabolic cost may be a fundamental feature of motor adaptation.

Reductions in muscle coactivation and metabolic cost during visuomotor adaptation.

We often have to adapt our movements as we interact with a variety of objects in various conditions on a daily basis. Evidence suggests that motor adaptation relies on a process that minimizes error and effort; however, much of this evidence involved adapting to novel dynamics with physical perturbations to counteract. To examine the generality of the process of minimizing error and effort during motor adaptation, we used a visuomotor adaptation task that did not involve dynamic perturbations. We investigated the time courses of muscle activity, coactivation, and metabolic cost as subjects reached to a target with a visuomotor rotation. We wanted to determine whether subjects would modulate muscle activity, coactivation, and metabolic cost during a visuomotor adaptation task. Interestingly, subjects increased muscle coactivation early during visuomotor adaptation when there were large cursor-trajectory errors but no physical perturbations to reject. As adaptation progressed, muscle activity and coactivation decreased. Metabolic cost followed a similar time course. When the perturbation was removed, typical after-effects were observed: trajectory error increased and then was reduced quickly. This was accompanied by increases in muscle activity, coactivation, and metabolic cost, along with subsequent rapid reductions. These results demonstrate that subjects modulate muscle activity, coactivation, and metabolic cost similarly across different forms of motor adaptation. Overall, our findings suggest that minimization of error and effort may be a general process underlying various forms of motor adaptation.

Whose Signals Are Being Amplified? Toward a More Equitable Clinical Psychophysiology.

Research using psychophysiological methods holds great promise for refining clinical assessment, identifying risk factors, and informing treatment. Unfortunately, unique methodological features of existing approaches limit inclusive research participation and, consequently, generalizability. This brief overview and commentary provides a snapshot of the current state of representation in clinical psychophysiology, with a focus on the forms and consequences of ongoing exclusion of Black participants. We illustrate issues of inequity and exclusion that are unique to clinical psychophysiology, considering intersections among social constructions of Blackness and biased design of current technology used to measure electroencephalography, skin conductance, and other signals. We then highlight work by groups dedicated to quantifying and addressing these limitations. We discuss the need for reflection and input from a wider variety of stakeholders to develop and refine new technologies, given the risk of further widening disparities. Finally, we provide broad recommendations for clinical psychophysiology research.

Reduction of metabolic cost during motor learning of arm reaching dynamics.

It is often assumed that the CNS controls movements in a manner that minimizes energetic cost. While empirical evidence for actual metabolic minimization exists in locomotion, actual metabolic cost has yet to be measured during motor learning and/or arm reaching. Here, we measured metabolic power consumption using expired gas analysis, as humans learned novel arm reaching dynamics. We hypothesized that (1) metabolic power would decrease with motor learning and (2) muscle activity and coactivation would parallel changes in metabolic power. Seated subjects made horizontal planar reaching movements toward a target using a robotic arm. The novel dynamics involved compensating for a viscous curl force field that perturbed reaching movements. Metabolic power was measured continuously throughout the protocol. Subjects decreased movement error and learned the novel dynamics. By the end of learning, net metabolic power decreased by ~20% (~0.1 W/kg) from initial learning. Muscle activity and coactivation also decreased with motor learning. Interestingly, distinct and significant reductions in metabolic power occurred even after muscle activity and coactivation had stabilized and movement changes were small. These results provide the first evidence of actual metabolic reduction during motor learning and for a reaching task. Further, they suggest that muscle activity may not explain changes in metabolic cost as completely as previously thought. Additional mechanisms such as more subtle features of arm muscle activity, changes in activity of other muscles, and/or more efficient neural processes may also underlie the reduction in metabolic cost during motor learning.

Speeding up: Discrete mediolateral perturbations increased self-paced walking speed in young and older adults.

BACKGROUND: In uncertain environments and with increasing age, humans often walk, slower while taking shorter, quicker, and wider steps, reflective of a cautious gait., Understanding when humans opt to use a cautious gait and the differences in gait, strategies used as people age could be examined with perturbations on a self-paced, treadmill that allows participants to adjust their walking speed. Adding varying degrees, of unpredictability, an inherent element of real-world walking, could also improve, understanding of when specific gait strategies are used RESEARCH QUESTION: We investigated how healthy young and older adults adjust their, gait strategies when responding to perturbations of varying unpredictability. We, hypothesized that more unpredictable perturbations would produce more cautious gait, strategies and be more pronounced in older adults than young adults METHODS: Ten young and ten older adults walked on a self-paced treadmill with, discrete mediolateral treadmill shift perturbations. We changed the shift magnitude, and/or the timing of the perturbations during the gait cycle to vary perturbation, unpredictability. We analyzed walking speed and step kinematics from treadmill and, motion capture data RESULTS: Surprisingly, participants walked faster, not slower, for the conditions with, perturbations. Even more surprising, older adults walked faster overall than young, adults. As expected, participants took faster and wider steps for the most unpredictable, perturbation but also took longer steps, which was not expected. Step kinematic, variability and average step width also increased as perturbation unpredictability, increased, suggesting that the more unpredictable conditions demanded greater, balance control. Additionally, older adults had greater step kinematic variability, highlighted further using detrended step length variability, compared to young adults SIGNIFICANCE: Overall, these findings provide new insights about gait strategies and, suggest that perturbations such as discrete mediolateral treadmill shifts can potentially, be designed to encourage participants to walk faster, if it is beneficial.

Step-to-step variability indicates disruption to balance control when linking the arms and legs during treadmill walking.

We recently discovered that a rope-pulley system that mechanically coupling the arms, legs and treadmill during walking can assist with forward propulsion in healthy subjects, leading to significant reductions in metabolic cost. However, walking balance may have been compromised, which could hinder the potential use of this device for gait rehabilitation. We performed a secondary analysis by quantifying average step width, step length, and step time, and used their variability to reflect simple metrics of walking balance (n = 8). We predicted an increased variability in at least one of these metrics when using the device, which would indicate disruptions to walking balance. When walking with the device, subjects increased their average step width (p < 0.05), but variability in step width and step length remained similar (p's > 0.05). However, the effect size for step length variability when compared to that of mechanical perturbation experiments suggest a minimal to moderate disruption in balance (Rosenthal ES = 0.385). The most notable decrement in walking balance was an increase in step time variability (p < 0.05; Cohen's d = 1.286). Its effect size reveals a moderate disruption when compared to the effect sizes observed in those with balance deficits (effect sizes ranged between 0.486 to 1.509). Overall, we conclude that healthy subjects experienced minimal to moderate disruptions in walking balance when using with this device. These data indicate that in future clinical experiments, it will be important to not only consider the mechanical and metabolic effects of using such a device but also its potential to disrupt walking balance, which may be exacerbated in patients with poor balance control.

Longitudinal Monitoring of Circulating Tumor DNA to Predict Treatment Outcomes in Advanced Cancers.

PURPOSE: The response to cancer therapies is typically assessed with radiologic imaging 6-10 weeks after treatment initiation. Circulating tumor DNA (ctDNA), however, has a short half-life, and dynamic changes in ctDNA quantity may allow for earlier assessment of the therapeutic response. METHODS: Patients with advanced solid tumors referred to the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center were invited to participate in a liquid biopsy protocol for which serial blood samples were collected before, during, and after systemic therapy. We isolated ctDNA from serially collected plasma samples at baseline, mid-treatment, and first restaging. Genomically informed droplet digital polymerase chain reaction (ddPCR) was performed, and ctDNA quantities were reported as aggregate variant allele frequencies for all detected molecular aberrations. RESULTS: We included 204 patients receiving 260 systemic therapies. The ctDNA detection rate was higher in progressors (patients with progressive disease) compared with nonprogressors (patients with stable disease, partial responses, or complete responses) at all time points (P < .009). Moreover, ctDNA detection was associated with a shorter median time-to-treatment failure (P ≤ .001). Positive delta and slope values for changes in ctDNA quantity were more frequent in progressors (P ≤ .03 and P < .001, respectively) and were associated with a shorter median time-to-treatment failure (P ≤ .014 and P < .001, respectively). Increasing ctDNA quantity was predictive of clinical and/or radiologic progressive disease in 73% of patients (median lead time, 23 days). CONCLUSION: Detection of ctDNA and early dynamic changes in its quantity can predict the clinical outcomes of systemic therapies in patients with advanced solid tumors.

Monitoring of Dynamic Changes and Clonal Evolution in Circulating Tumor DNA From Patients With IDH-Mutated Cholangiocarcinoma Treated With Isocitrate Dehydrogenase Inhibitors.

PURPOSE: IDH mutations occur in about 30% of patients with cholangiocarcinoma. Analysis of mutations in circulating tumor DNA (ctDNA) can be performed by droplet digital polymerase chain reaction (ddPCR). The analysis of ctDNA is a feasible approach to detect IDH mutations. METHODS: We isolated ctDNA from the blood of patients with IDH-mutated advanced cholangiocarcinoma collected at baseline, on therapy, and at progression to isocitrate dehydrogenase (IDH) inhibitors. RESULTS: Of 31 patients with IDH1R132 (n = 26) or IDH2R172 mutations (n = 5) in the tumor, IDH mutations were detected in 84% of ctDNA samples analyzed by ddPCR and in 83% of ctDNA samples analyzed by next-generation sequencing (NGS). Patients with a low variant allele frequency of ctDNA detected by NGS at baseline had a longer median time to treatment failure compared to patients with high variant allele frequency of ctDNA (3.6 v 1.5 months; P = .008). Patients with a decrease in IDH-mutated ctDNA on therapy by ddPCR compared with no change/increase had a trend to a longer median survival (P = .07). Most frequent emergent alterations in ctDNA by NGS at progression were ARID1A (n = 3) and TP53 mutations (n = 3). CONCLUSION: Detection of IDH mutations in ctDNA in patients with advanced cholangiocarcinoma is feasible, and dynamic changes in ctDNA can correspond with the clinical course and clonal evolution.

Speed-related but not detrended gait variability increases with more sensitive self-paced treadmill controllers at multiple slopes.

Self-paced treadmills are being used more frequently to study humans walking with their self-selected gaits on a range of slopes. There are multiple options to purchase a treadmill with a built-in controller, or implement a custom written self-paced controller, which raises questions about how self-paced controller affect treadmill speed and gait biomechanics on multiple slopes. This study investigated how different self-paced treadmill controller sensitivities affected gait parameters and variability on decline, level, and incline slopes. We hypothesized that increasing self-paced controller sensitivity would increase gait variability on each slope. We also hypothesized that detrended variability could help mitigate differences in variability that arise from differences in speed fluctuations created by the self-paced controllers. Ten young adults walked on a self-paced treadmill using three controller sensitivities (low, medium, and high) and fixed speeds at three slopes (decline, -10°; level, 0°; incline, +10°). Within each slope, average walking speeds and spatiotemporal gait parameters were similar regardless of self-paced controller sensitivity. With higher controller sensitivities on each slope, speed fluctuations, speed variance, and step length variance increased whereas step frequency variance and step width variance were unaffected. Detrended variance was not affected by controller sensitivity suggesting that detrending variability helps mitigate differences associated with treadmill speed fluctuations. Speed-trend step length variances, however, increased with more sensitive controllers. Further, detrended step length variances were similar for self-paced and fixed speed walking, whereas self-paced walking included substantial speed-trend step length variance not present in fixed speed walking. In addition, regardless of the self-paced controller, subjects walked fastest on the level slope with the longest steps, narrowest steps, and least variance. Overall, our findings suggest that separating gait variability into speed-trend and detrended variability could be beneficial for interpreting gait variability among multiple self-paced treadmill studies and when comparing self-paced walking with fixed speed walking.