A Portable, Neurostimulation-Integrated, Force Measurement Platform for the Clinical Assessment of Plantarflexor Central Drive.

Plantarflexor central drive is a promising biomarker of neuromotor impairment; however, routine clinical assessment is hindered by the unavailability of force measurement systems with integrated neurostimulation capabilities. In this study, we evaluate the accuracy of a portable, neurostimulation-integrated, plantarflexor force measurement system we developed to facilitate the assessment of plantarflexor neuromotor function in clinical settings. Two experiments were conducted with the Central Drive System (CEDRS). To evaluate accuracy, experiment #1 included 16 neurotypical adults and used intra-class correlation (ICC2,1) to test agreement of plantarflexor strength capacity measured with CEDRS versus a stationary dynamometer. To evaluate validity, experiment #2 added 26 individuals with post-stroke hemiparesis and used one-way ANOVAs to test for between-limb differences in CEDRS' measurements of plantarflexor neuromotor function, comparing neurotypical, non-paretic, and paretic limb measurements. The association between paretic plantarflexor neuromotor function and walking function outcomes derived from the six-minute walk test (6MWT) were also evaluated. CEDRS' measurements of plantarflexor neuromotor function showed high agreement with measurements made by the stationary dynamometer (ICC = 0.83, p < 0.001). CEDRS' measurements also showed the expected between-limb differences (p's < 0.001) in maximum voluntary strength (Neurotypical: 76.21 ± 13.84 ft-lbs., Non-paretic: 56.93 ± 17.75 ft-lbs., and Paretic: 31.51 ± 14.08 ft-lbs.), strength capacity (Neurotypical: 76.47 ± 13.59 ft-lbs., Non-paretic: 64.08 ± 14.50 ft-lbs., and Paretic: 44.55 ± 14.23 ft-lbs.), and central drive (Neurotypical: 88.73 ± 1.71%, Non-paretic: 73.66% ± 17.74%, and Paretic: 52.04% ± 20.22%). CEDRS-measured plantarflexor central drive was moderately correlated with 6MWT total distance (r = 0.69, p < 0.001) and distance-induced changes in speed (r = 0.61, p = 0.002). CEDRS is a clinician-operated, portable, neurostimulation-integrated force measurement platform that produces accurate measurements of plantarflexor neuromotor function that are associated with post-stroke walking ability.

Imatinib Resistance in Chronic Myeloid Leukemia Associated with a D363G BCR::ABL1 Kinase Domain Mutation.

Acquired resistance to tyrosine kinase inhibitors (TKIs) remains a therapeutic challenge in the treatment of chronic myeloid leukemia (CML). The most studied reason for TKI resistance is the acquisition of mutations within the BCR::ABL1 tyrosine kinase domain (KDM) and of which the majority of which occur at seven codons within this region. A case of CML is described in which presence of a rare D363G BCR::ABL1 KDM resulted in a suboptimal response to frontline imatinib. Switching to dasatinib resulted in achieving a sustained major molecular response that was maintained after a subsequent switch to bosutinib due to the side effects. Reporting of such cases is important for the future management of any CML patients with this rare mutation.

Excellence in Academic Physical Therapy: Promoting a Culture of Data Sharing.

BACKGROUND AND PURPOSE: Data analytics are increasingly important in health professions education to identify trends and inform organizational change in rapidly evolving environments. Unfortunately, limitations exist in data currently available to determine physical therapy (PT) academic excellence. It is imperative that the American Council of Academic Physical Therapy (ACAPT) be able to demonstrate data-informed progress in addressing the common challenges faced by Doctor of Physical Therapy programs. POSITION AND RATIONALE: The Task Force to Explore Data and Technology to Evaluate Program Outcomes was convened by ACAPT to explore current and desired data and the needs, technology, and costs that would be required for ACAPT to assess program outcomes relative to excellence criteria. The Task Force performed a gap analysis of measures of excellence, provided evidence-based recommendations for advancing the use of data and technology systems in academic PT, and generated a comprehensive Assessment Excellence Map that subsequently led to a new streamlined Excellence Framework in the launch of the ACAPT Center for Excellence. DISCUSSION AND CONCLUSION: The vision of universal excellence in PT education necessitates clear alignment and centralization of common data to support efficient processes to assess excellence. The transformative nature of data is untapped in PT academic endeavors, and nascent work to establish and sustain a culture of centralized data sharing and assessment will help to drive program-level and profession-level excellence in PT education.

Ankle stiffness modulation during different gait speeds in individuals post-stroke.

BACKGROUND: Neurotypical individuals alter their ankle joint quasi-stiffness in response to changing walking speed; however, for individuals post-stroke, the ability to alter their ankle quasi-stiffness is unknown. Individuals post-stroke commonly have weak plantarflexor muscles, which may limit their ability to alter ankle quasi-stiffness. The objective was to investigate the relationship between ankle quasi-stiffness and propulsion, at two walking speeds. We hypothesized that in individuals post-stroke, there would be no difference in their paretic ankle quasi-stiffness between walking at a self-selected versus a fast speed. However, we hypothesized that ankle quasi-stiffness would correlate with gait speed and propulsion across individuals. METHODS: Twenty-eight participants with chronic stroke walked on an instrumented treadmill at their self-selected and fast-walking speeds. Multilevel models were used to determine the relationships between ankle quasi-stiffness, speed, and propulsion. FINDINGS: Overall, ankle quasi-stiffness did not increase within individuals from a self-selected to a fast gait speed (p = 0.69). A 1 m/s increase in speed across participants predicted an increase in overall ankle quasi-stiffness of 0.02 Nm/deg./kg (p = 0.03) and a 1 N/BW change in overall propulsion across participants predicted a 0.265 Nm/deg./kg increase in overall ankle quasi-stiffness (p < 0.0001). INTERPRETATION: Individuals post-stroke did not modulate their ankle quasi-stiffness with increased speed, but across individuals there was a positive relationship between ankle quasi-stiffness and both speed and peak propulsion. Walking speed and propulsion are limited in individuals post-stroke, therefore, improving either could lead to a higher functional status. Understanding post-stroke ankle stiffness may be important in the design of therapeutic interventions and exoskeletons, where these devices augment the biological ankle quasi-stiffness to improve walking performance.

What I Know: The Value of Mentoring and Leadership.

Stuart Binder-Macleod, PT, PhD, FAPTA, the 51st Mary McMillan lecturer, is the Edward L. Ratledge Professor of Physical Therapy and associate vice president for clinical and translation research at the University of Delaware (UD). He served as the chair of UD's department of physical therapy for 16 years, and his research laboratory had more than 25 years of continuous National Institutes of Health funding, including major funding for projects involving the development and testing of treatment interventions for individuals demonstrating poststroke hemiparesis. A recipient of multiple honors from the American Physical Therapy Association (APTA) and its components, Binder-Macleod also served on the task force that created the American Council of Academic Physical Therapy, and he currently serves on the Board of Trustees of the Foundation for Physical Therapy Research.

Central Drive to the Paretic Ankle Plantarflexors Affects the Relationship Between Propulsion and Walking Speed After Stroke.

BACKGROUND AND PURPOSE: The ankle plantarflexor muscles are the primary generators of propulsion during walking. Impaired paretic plantarflexion is a key contributor to interlimb propulsion asymmetry after stroke. Poststroke muscle weakness may be the result of a reduced force-generating capacity, reduced central drive, or a combination of these impairments. This study sought to elucidate the relationship between the neuromuscular function of the paretic plantarflexor muscles and propulsion deficits across individuals with different walking speeds. METHODS: For 40 individuals poststroke, we used instrumented gait analysis and dynamometry coupled with supramaximal electrostimulation to study the interplay between limb kinematics, the neuromuscular function of the paretic plantarflexors (ie, strength capacity and central drive), propulsion, and walking speed. RESULTS: The strength capacity of the paretic plantarflexors was not independently related to paretic propulsion. Reduced central drive to the paretic plantarflexors independently contributed to paretic propulsion deficits. An interaction between walking speed and plantarflexor central drive was observed. Individuals with slower speeds and lower paretic plantarflexor central drive presented with the largest propulsion impairments. Some study participants with low paretic plantarflexor central drive presented with similarly fast speeds as those with near-normal central drive by leveraging a compensatory reliance on nonparetic propulsion. The final model accounted for 86% of the variance in paretic propulsion (R = 0.86, F = 33.10, P < 0.001). DISCUSSION AND CONCLUSIONS: Individuals poststroke have latent paretic plantarflexion strength that they are not able to voluntarily access. The magnitude of central drive deficit is a strong indicator of propulsion impairment in both slow and fast walkers.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A298).

Distance-Induced Changes in Walking Speed After Stroke: Relationship to Community Walking Activity.

BACKGROUND AND PURPOSE: Physical inactivity is a major contributing factor to reduced health and quality of life. The total distance walked during the 6-Minute Walk Test is a strong indicator of real-world walking activity after stroke. The purpose of this study was to determine whether measurement of distance-induced changes in walking speed during the 6-Minute Walk Test improves the test's ability to predict community walking activity. METHODS: For 40 individuals poststroke, community walking activity (steps/d), the total distance walked during the 6-Minute Walk Test (6MWTtotal), and the difference between the distances walked during the final and first minutes of the test (Δ6MWTmin6-min1) were analyzed using moderated regression. Self-efficacy, assessed using the Activities-specific Balance Confidence scale, was also included in the model. RESULTS: Alone, 6MWTtotal explained 41% of the variance in steps/d. The addition of Δ6MWTmin6-min1 increased explanatory power by 29% (ΔR = 0.29, P < 0.001). The final model accounted for 71% of steps/d variance (F4,32 = 19.52, P < 0.001). Examination of a significant 6MWTtotal × Δ6MWTmin6-min1 interaction revealed a positive relationship between 6MWTtotal and steps/d, with individuals whose distances declined from minute 1 to minute 6 by 0.10 m/s or more presenting with substantially fewer steps/d than those whose distances did not decline. DISCUSSION AND CONCLUSIONS: Coassessment of distance-induced changes in walking speed during the 6-Minute Walk Test and the total distance walked substantially improves the prediction of real-world walking activity after stroke. This study provides new insight into how walking ability after stroke can be characterized to reduce heterogeneity and advance personalized treatments.

Stimulation of paralysed quadriceps muscles with sequentially and spatially distributed electrodes during dynamic knee extension.

BACKGROUND: During functional electrical stimulation (FES) tasks with able-bodied (AB) participants, spatially distributed sequential stimulation (SDSS) has demonstrated substantial improvements in power output and fatigue properties compared to conventional single electrode stimulation (SES). The aim of this study was to compare the properties of SDSS and SES in participants with spinal cord injury (SCI) in a dynamic isokinetic knee extension task simulating knee movement during recumbent cycling. METHOD: Using a case-series design, m. vastus lateralis and medialis of four participants with motor and sensory complete SCI (AIS A) were stimulated for 6 min on both legs with both electrode setups. With SES, target muscles were stimulated by a pair of electrodes. In SDSS, the distal electrodes were replaced by four small electrodes giving the same overall stimulation frequency and having the same total surface area. Torque was measured during knee extension by a dynamometer at an angular velocity of 110 deg/s. Mean power of the left and right sides (PmeanL,R) was calculated from all stimulated extensions for initial, final and all extensions. Fatigue is presented as an index value with respect to initial power from 1 to 0, whereby 1 means no fatigue. RESULTS: SDSS showed higher PmeanL,R values for all four participants for all extensions (increases of 132% in participant P1, 100% in P2, 36% in P3 and 18% in P4 compared to SES) and for the initial phase (increases of 84%, 59%, 66%, and 16%, respectively). Fatigue resistance was better with SDSS for P1, P2 and P4 but worse for P3 (0.47 vs 0.35, 0.63 vs 0.49, 0.90 vs 0.82 and 0.59 vs 0.77, respectively). CONCLUSION: Consistently higher PmeanL,R was observed for all four participants for initial and overall contractions using SDSS. This supports findings from previous studies with AB participants. Fatigue properties were better in three of the four participants. The lower fatigue resistance with SDSS in one participant may be explained by a very low muscle activation level in this case. Further investigation in a larger cohort is warranted.

1978: Forty years later.

Think back; think wayyy back: before laptops, internet and smartphones. Bank machines didn't exist, tele-phones were permanently plugged into the wall, airport security meant only checking that you paid for your ticket and medical journals came in the mail (as did the bills for the journals). As it turned out, the 1970s was not a kind decade for medical journals, and several were struggling financially. Even the New England Journal of Medicine (NEJM), desperate for cash, was forced to offer a lifetime subscription to anyone who could pay the princely sum of $350! (A colleague of ours, now retired, still receives the weekly NEJM by mail, 45 years later!).

CSCI and the future of clinical health science research in Canada.

In 2003, Dr. MacLeod became Professor (emeritus since 2014) in the Department of Pediatrics, University of British Columbia and Director of the BC Children's Hospital Research Institute. Previously, he had spent 14 years as a clinical pharmacologist at the University of Toronto and The Hospital for Sick Children and was Dean of the Faculty of Health Sciences, McMaster University 1987-1992. His research interests include pediatric clinical pharmacology, treatments for rare disorders, global health and medical education. From 1984-85, he was President of the Canadian Society for Clinical Investigation.

High-throughput DNA Extraction and Genotyping of 3dpf Zebrafish Larvae by Fin Clipping.

Zebrafish (Danio rerio) possess orthologues for 84% of the genes known to be associated with human diseases. In addition, these animals have a short generation time, are easy to handle, display a high reproductive rate, low cost, and are easily amenable to genetic manipulations by microinjection of DNA in embryos. Recent advances in gene editing tools are enabling precise introduction of mutations and transgenes in zebrafish. Disease modeling in zebrafish often leads to larval phenotypes and early death which can be challenging to interpret if genotypes are unknown. This early identification of genotypes is also needed in experiments requiring sample pooling, such as in gene expression or mass spectrometry studies. However, extensive genotypic screening is limited by traditional methods, which in most labs are performed only on adult zebrafish or in postmortem larvae. We addressed this problem by adapting a method for the isolation of PCR-ready genomic DNA from live zebrafish larvae that can be achieved as early as 72 h post-fertilization (hpf). This time and cost-effective technique, improved from a previously published genotyping protocol, allows the identification of genotypes from microscopic fin biopsies. The fins quickly regenerate as the larvae develop. Researchers are then able to select and raise the desired genotypes to adulthood by utilizing this high-throughput PCR-based genotyping procedure.

Key Challenges in the Search for Innovative Drug Treatments for Special Populations. Converging Needs in Neonatology, Pediatrics, and Medical Genetics.

The explosion of knowledge concerning the interplay of genetic and environmental factors determining pathophysiology and guiding therapeutic choice has altered the landscape in pediatric clinical pharmacology and pharmacy. The need for innovative research methods and design expertise for small clinical trials to be undertaken in sparse populations has been accentuated. At the same time, shortfalls in critical human resources represent a key challenge, especially in low- and middle-income countries where the need for new research and education directions is greatest. Unless a specific action plan is urgently developed, there will be a continuing gap in availability of the essential expertise needed to address treatment challenges in special patient populations such as neonates, patients suffering from rare or neglected diseases, and children of all ages.

Power output and fatigue properties using spatially distributed sequential stimulation in a dynamic knee extension task.

PURPOSE: The low power output and fatigue resistance during functional electrical stimulation (FES) limits its use for functional applications. The aim of this study was to compare the power output and fatigue properties of spatially distributed sequential stimulation (SDSS) against conventional single electrode stimulation (SES) in an isokinetic knee extension task simulating knee movement during recumbent cycling. METHODS: M. vastus lateralis and m. vastus medialis of eight able-bodied subjects were stimulated for 6 min on both legs with both setups. In the SES setup, target muscles were each stimulated by a pair of electrodes. In SDSS, four small electrodes replaced the SES active electrodes, but reference electrodes were the same. Torque was measured during knee extension movement by a dynamometer at an angular velocity of 110°/s. Mean power (P mean) was calculated from stimulated extensions for the first 10 extensions, the final 20 extensions and overall. Fatigue is presented as an index, calculated as the decrease with respect to initial power. RESULTS: P mean was significantly higher for SDSS than for SES in the final phase (9.9 ± 4.0 vs. 7.4 ± 4.3 W, p = 0.035) and overall (11.5 ± 4.0 vs. 9.2 ± 4.5 W, p =  0.037). With SDSS, the reduction in P mean was significantly smaller compared to SES (from 14.9 to 9.9 vs. 14.6 to 7.4 W, p = 0.024). The absolute mean pulse width was substantially lower with SDSS (62.5 vs. 90.0 µs). CONCLUSION: Although less stimulation was applied, SDSS showed a significantly higher mean power output than SES. SDSS also had improved fatigue resistance when compared to conventional stimulation. The SDSS approach may provide substantial performance benefits for cyclical FES applications.

Control of lateral weight transfer is associated with walking speed in individuals post-stroke.

Restoring functional gait speed is an important goal for rehabilitation post-stroke. During walking, transferring of one's body weight between the limbs and maintaining balance stability are necessary for independent functional gait. Although it is documented that individuals post-stroke commonly have difficulties with performing weight transfer onto their paretic limbs, it remains to be determined if these deficits contributed to slower walking speeds. The primary purpose of this study was to compare the weight transfer characteristics between slow and fast post-stroke ambulators. Participants (N=36) with chronic post-stroke hemiparesis walked at their comfortable and maximal walking speeds on a treadmill. Participants were stratified into 2 groups based on their comfortable walking speeds (≥0.8m/s or <0.8m/s). Minimum body center of mass (COM) to center of pressure (COP) distance, weight transfer timing, step width, lateral foot placement relative to the COM, hip moment, peak vertical and anterior ground reaction forces, and changes in walking speed were analyzed. Results showed that slow walkers walked with a delayed and deficient weight transfer to the paretic limb, lower hip abductor moment, and more lateral paretic limb foot placement relative to the COM compared to fast walkers. In addition, propulsive force and walking speed capacity was related to lateral weight transfer ability. These findings demonstrated that deficits in lateral weight transfer and stability could potentially be one of the limiting factors underlying comfortable walking speeds and a determinant of chronic stroke survivors' ability to increase walking speed.

Comparison of techniques to determine human skeletal muscle voluntary activation.

Determining volitional activation (VA) can provide insights on the cause of muscle weakness in orthopedic and neurological populations. Two electrical stimulation techniques are traditionally used to quantify VA: interpolation (IT) and superimposition (CAR). IT allows for a more accurate VA estimation, however it requires individuals to be stimulated twice, compared to once for CAR, and thus increases stimulation associated discomfort. To date, there is no agreement on what is the best practical technique for calculating quadriceps VA. This paper aims to address this problem by determining what reference force (i.e., using either peak force or force at the time of stimulation) and type of stimulation (train of pulses (burst), doublet, and twitch) is the best technique to use. Our findings showed that the IT with the force at the time of stimulation as a reference should be used to determine VA and that when a burst was used, the VA ratio computations were more accurate. Additionally, using a twitch with a 2ms pulse duration produced reliable VA calculations and may be an acceptable alternative for pain-sensitive subjects. Accurate assessment of VA deficits can help clinicians design rehabilitation programs that are based on subject-specific strength impairments and are more effective.

Single Session of Functional Electrical Stimulation-Assisted Walking Produces Corticomotor Symmetry Changes Related to Changes in Poststroke Walking Mechanics.

BACKGROUND: Recent research demonstrated that the symmetry of corticomotor drive with the paretic and nonparetic plantarflexor muscles was related to the biomechanical ankle moment strategy that people with chronic stroke used to achieve their greatest walking speeds. Rehabilitation strategies that promote corticomotor balance might improve poststroke walking mechanics and enhance functional ambulation. OBJECTIVE: The study objectives were to test the effectiveness of a single session of gait training using functional electrical stimulation (FES) to improve plantarflexor corticomotor symmetry and plantarflexion ankle moment symmetry and to determine whether changes in corticomotor symmetry were related to changes in ankle moment symmetry within the session. DESIGN: This was a repeated-measures crossover study. METHODS: On separate days, 20 people with chronic stroke completed a session of treadmill walking either with or without the use of FES of their ankle dorsi- and plantarflexor muscles. We calculated plantarflexor corticomotor symmetry using transcranial magnetic stimulation and plantarflexion ankle moment symmetry during walking between the paretic and the nonparetic limbs before and after each session. We compared changes and tested relationships between corticomotor symmetry and ankle moment symmetry following each session. RESULTS: Following the session with FES, there was an increase in plantarflexor corticomotor symmetry that was related to the observed increase in ankle moment symmetry. In contrast, following the session without FES, there were no changes in corticomotor symmetry or ankle moment symmetry. LIMITATIONS: No stratification was made on the basis of lesion size, location, or clinical severity. CONCLUSIONS: These findings demonstrate, for the first time (to our knowledge), the ability of a single session of gait training with FES to induce positive corticomotor plasticity in people in the chronic stage of stroke recovery. They also provide insight into the neurophysiologic mechanisms underlying improvements in biomechanical walking function.

Characterizing differential poststroke corticomotor drive to the dorsi- and plantarflexor muscles during resting and volitional muscle activation.

Imbalance of corticomotor excitability between the paretic and nonparetic limbs has been associated with the extent of upper extremity motor recovery poststroke, is greatly influenced by specific testing conditions such as the presence or absence of volitional muscle activation, and may vary across muscle groups. However, despite its clinical importance, poststroke corticomotor drive to lower extremity muscles has not been thoroughly investigated. Additionally, whereas conventional gait rehabilitation strategies for stroke survivors focus on paretic limb foot drop and dorsiflexion impairments, most contemporary literature has indicated that paretic limb propulsion and plantarflexion impairments are the most significant limiters to poststroke walking function. The purpose of this study was to compare corticomotor excitability of the dorsi- and plantarflexor muscles during resting and active conditions in individuals with good and poor poststroke walking recovery and in neurologically intact controls. We found that plantarflexor muscles showed reduced corticomotor symmetry between paretic and nonparetic limbs compared with dorsiflexor muscles in individuals with poor poststroke walking recovery during active muscle contraction but not during rest. Reduced plantarflexor corticomotor symmetry during active muscle contraction was a result of reduced corticomotor drive to the paretic muscles and enhanced corticomotor drive to the nonparetic muscles compared with the neurologically intact controls. These results demonstrate that atypical corticomotor drive exists in both the paretic and nonparetic lower limbs and implicate greater severity of corticomotor impairments to plantarflexor vs. dorsiflexor muscles during muscle activation in stroke survivors with poor walking recovery.NEW & NOTEWORTHY The present study observed that lower-limb corticomotor asymmetry resulted from both reduced paretic and enhanced nonparetic limb corticomotor excitability compared with neurologically intact controls. The most asymmetrical corticomotor drive was observed in the plantarflexor muscles of individuals with poor poststroke walking recovery. This suggests that neural function of dorsi- and plantarflexor muscles in both paretic and nonparetic limbs may play a role in poststroke walking function, which may have important implications when developing targeted poststroke rehabilitation programs to improve walking ability.