Attenuation of muscle spindle firing with artificially increased series compliance during stretch of relaxed muscle.

Muscle spindles relay vital mechanosensory information for movement and posture, but muscle spindle feedback is coupled to skeletal motion by a compliant tendon. Little is known about the effects of tendon compliance on muscle spindle feedback during movement, and the complex firing of muscle spindles makes these effects difficult to predict. Our goal was to investigate changes in muscle spindle firing using added series elastic elements (SEEs) to mimic a more compliant tendon, and to characterize the accompanying changes in firing with respect to muscle-tendon unit (MTU) and muscle fascicle displacements (recorded via sonomicrometry). Sinusoidal, ramp-and-hold and triangular stretches were analysed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor- and perturbation-like stretches as well as serial history dependence. Added SEEs effectively reduced overall MTU stiffness and generally reduced muscle spindle firing rates, but the effect differed across stretch types. During sinusoidal stretches, peak and mean firing rates were not reduced and IFR was best-correlated with fascicle velocity. During ramp stretches, SEEs reduced the initial burst, dynamic and static responses of the spindle. Notably, IFR was negatively related to fascicle displacement during the hold phase. During triangular stretches, SEEs reduced the mean IFR during the first and second stretches, affecting the serial history dependence of mean IFR. Overall, these results demonstrate that tendon compliance may attenuate muscle spindle feedback during movement, but these changes cannot be fully explained by reduced muscle fascicle length or velocity, or MTU force.

Perturbing the muscle work loop paradigm to unravel the neuromechanics of unsteady locomotion.

Muscle function during movement is more than a simple, linear transformation of neural activity into force. The classic work loop technique has pioneered our understanding of muscle, but typically only characterizes function during unperturbed movement cycles, such as those experienced during steady walking, running, swimming and flying. Yet perturbations away from steady movement often place greater demands on muscle structure and function and offer a unique window into muscle's broader capacity. Recently, studies in diverse organisms from cockroaches to humans have started to grapple with muscle function in unsteady (perturbed, transient and fluctuating) conditions, but the vast range of possible parameters and the challenge of connecting in vitro to in vivo experiments are daunting. Here, we review and organize these studies into two broad approaches that extend the classic work loop paradigm. First, in the top-down approach, researchers record length and activation patterns of natural locomotion under perturbed conditions, replay these conditions in isolated muscle work loop experiments to reveal the mechanism by which muscle mediates a change in body dynamics and, finally, generalize across conditions and scale. Second, in the bottom-up approach, researchers start with an isolated muscle work loop and then add structural complexity, simulated loads and neural feedback to ultimately emulate the muscle's neuromechanical context during perturbed movement. In isolation, each of these approaches has several limitations, but new models and experimental methods coupled with the formal language of control theory give several avenues for synthesizing an understanding of muscle function under unsteady conditions.

Linking whole-body angular momentum and step placement during perturbed human walking.

Human locomotion is remarkably robust to environmental disturbances. Previous studies have thoroughly investigated how perturbations influence body dynamics and what recovery strategies are used to regain balance. Fewer studies have attempted to establish formal links between balance and the recovery strategies that are executed to regain stability. We hypothesized that there would be a strong relationship between the magnitude of imbalance and recovery strategy during perturbed walking. To test this hypothesis, we applied transient ground surface translations that varied in magnitude, direction and onset time while 11 healthy participants walked on a treadmill. We measured stability using integrated whole-body angular momentum (iWBAM) and recovery strategy using step placement. We found the strongest relationships between iWBAM and step placement in the frontal plane for earlier perturbation onset times in the perturbed step (R2=0.52, 0.50) and later perturbation onset times in the recovery step (R2=0.18, 0.25), while correlations were very weak in the sagittal plane (all R2≤0.13). These findings suggest that iWBAM influences step placement, particularly in the frontal plane, and that this influence is sensitive to perturbation onset time. Lastly, this investigation is accompanied by an open-source dataset to facilitate research on balance and recovery strategies in response to multifactorial ground surface perturbations, including 96 perturbation conditions spanning all combinations of three magnitudes, eight directions and four gait cycle onset times.

Trajectories of the Transition Readiness Assessment Questionnaire Among Youth With Inflammatory Bowel Disease.

OBJECTIVE: The objective of this study was to describe in detail the trends of the Transition Readiness Assessment Questionnaire (TRAQ-20) with respect to patient age and gender among a cohort of 655 youth with inflammatory bowel disease (IBD) to enhance the tool's utility in clinical and research settings. MATERIALS AND METHODS: All participants in the Crohn's and Colitis Foundation's IBD Partners and IBD Partners Kids and Teens Cohorts ages 12 to 21 who completed the TRAQ-20 at least once were included. We computed centile scores for the TRAQ-20 and applied Kernel regression to generate curves. We computed mean scores for each TRAQ-20 domain by age for the overall cohort and stratified by gender. RESULTS: TRAQ-20 scores generally increase with age. Males have a steeper trajectory from ages 17 to 19 compared with females. By age 21, median overall TRAQ-20 scores for women and men were 4.4 and 4.7, respectively. The "Talking with Providers" domain of the TRAQ-20 had high scores throughout the age range of the cohort, while others had lower scores in younger ages and higher scores in older ages. All TRAQ-20 domains had mean scores of 4 or greater (out of a possible 5) among 21-year-olds. CONCLUSIONS: TRAQ-20 scores increase with age. The rate of increase varies by gender. Rates of increase also differ across domains. The use of transition readiness growth curves can help providers and researchers identify patients who are not achieving expected levels of transition readiness and determine the level of transition readiness that a patient much achieve before transfer to adult care.

Reduced Achilles Tendon Stiffness Disrupts Calf Muscle Neuromechanics in Elderly Gait.

Older adults walk slower and with a higher metabolic energy expenditure than younger adults. In this review, we explore the hypothesis that age-related declines in Achilles tendon stiffness increase the metabolic cost of walking due to less economical calf muscle contractions and increased proximal joint work. This viewpoint may motivate interventions to restore ankle muscle-tendon stiffness, improve walking mechanics, and reduce metabolic cost in older adults.

Ivacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation. Results of a Two-Part Phase 3 Clinical Trial.

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.Clinical trial registered with clinicaltrials.gov (NCT02725567).

Series elasticity facilitates safe plantar flexor muscle-tendon shock absorption during perturbed human hopping.

In our everyday lives, we negotiate complex and unpredictable environments. Yet, much of our knowledge regarding locomotion has come from studies conducted under steady-state conditions. We have previously shown that humans rely on the ankle joint to absorb energy and recover from perturbations; however, the muscle-tendon unit (MTU) behaviour and motor control strategies that accompany these joint-level responses are not yet understood. In this study, we determined how neuromuscular control and plantar flexor MTU dynamics are modulated to maintain stability during unexpected vertical perturbations. Participants performed steady-state hopping and, at an unknown time, we elicited an unexpected perturbation via rapid removal of a platform. In addition to kinematics and kinetics, we measured gastrocnemius and soleus muscle activations using electromyography and in vivo fascicle dynamics using B-mode ultrasound. Here, we show that an unexpected drop in ground height introduces an automatic phase shift in the timing of plantar flexor muscle activity relative to MTU length changes. This altered timing initiates a cascade of responses including increased MTU and fascicle length changes and increased muscle forces which, when taken together, enables the plantar flexors to effectively dissipate energy. Our results also show another mechanism, whereby increased co-activation of the plantar- and dorsiflexors enables shortening of the plantar flexor fascicles prior to ground contact. This co-activation improves the capacity of the plantar flexors to rapidly absorb energy upon ground contact, and may also aid in the avoidance of potentially damaging muscle strains. Our study provides novel insight into how humans alter their neural control to modulate in vivo muscle-tendon interaction dynamics in response to unexpected perturbations. These data provide essential insight to help guide design of lower-limb assistive devices that can perform within varied and unpredictable environments.

Reducing the energy cost of human walking using an unpowered exoskeleton.

With efficiencies derived from evolution, growth and learning, humans are very well-tuned for locomotion. Metabolic energy used during walking can be partly replaced by power input from an exoskeleton, but is it possible to reduce metabolic rate without providing an additional energy source? This would require an improvement in the efficiency of the human-machine system as a whole, and would be remarkable given the apparent optimality of human gait. Here we show that the metabolic rate of human walking can be reduced by an unpowered ankle exoskeleton. We built a lightweight elastic device that acts in parallel with the user's calf muscles, off-loading muscle force and thereby reducing the metabolic energy consumed in contractions. The device uses a mechanical clutch to hold a spring as it is stretched and relaxed by ankle movements when the foot is on the ground, helping to fulfil one function of the calf muscles and Achilles tendon. Unlike muscles, however, the clutch sustains force passively. The exoskeleton consumes no chemical or electrical energy and delivers no net positive mechanical work, yet reduces the metabolic cost of walking by 7.2 ± 2.6% for healthy human users under natural conditions, comparable to savings with powered devices. Improving upon walking economy in this way is analogous to altering the structure of the body such that it is more energy-effective at walking. While strong natural pressures have already shaped human locomotion, improvements in efficiency are still possible. Much remains to be learned about this seemingly simple behaviour.

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.

Cyclically producing the same average muscle-tendon force with a smaller duty increases metabolic rate.

Ground contact duration and stride frequency each affect muscle metabolism and help scientists link walking and running biomechanics to metabolic energy expenditure. While these parameters are often used independently, the product of ground contact duration and stride frequency (i.e. duty factor) may affect muscle contractile mechanics. Here, we sought to separate the metabolic influence of the duration of active force production, cycle frequency and duty factor. Human participants produced cyclic contractions using their soleus (which has a relatively homogeneous fibre type composition) at prescribed cycle-average ankle moments on a fixed dynamometer. Participants produced these ankle moments over short, medium and long durations while maintaining a constant cycle frequency. Overall, decreased duty factor did not affect cycle-average fascicle force (p ≥ 0.252) but did increase net metabolic power (p ≤ 0.022). Mechanistically, smaller duty factors increased maximum muscle-tendon force (p < 0.001), further stretching in-series tendons and shifting soleus fascicles to shorter lengths and faster velocities, thereby increasing soleus total active muscle volume (p < 0.001). Participant soleus total active muscle volume well-explained net metabolic power (r = 0.845; p < 0.001). Therefore, cyclically producing the same cycle-average muscle-tendon force using a decreased duty factor increases metabolic energy expenditure by eliciting less economical muscle contractile mechanics.

Impact of elastic ankle exoskeleton stiffness on neuromechanics and energetics of human walking across multiple speeds.

BACKGROUND: Elastic ankle exoskeletons with intermediate stiffness springs in parallel with the human plantarflexors can reduce the metabolic cost of walking by ~ 7% at 1.25 m s- 1. In a move toward 'real-world' application, we examined whether the unpowered approach has metabolic benefit across a range of walking speeds, and if so, whether the optimal exoskeleton stiffness was speed dependent. We hypothesized that, for any walking speed, there would be an optimal ankle exoskeleton stiffness - not too compliant and not too stiff - that minimizes the user's metabolic cost. In addition, we expected the optimal stiffness to increase with walking speed. METHODS: Eleven participants walked on a level treadmill at 1.25, 1.50, and 1.75 m s- 1 while we used a state-of-the-art exoskeleton emulator to apply bilateral ankle exoskeleton assistance at five controlled rotational stiffnesses (kexo = 0, 50, 100, 150, 250 Nm rad- 1). We measured metabolic cost, lower-limb joint mechanics, and EMG of muscles crossing the ankle, knee, and hip. RESULTS: Metabolic cost was significantly reduced at the lowest exoskeleton stiffness (50 Nm rad- 1) for assisted walking at both 1.25 (4.2%; p = 0.0162) and 1.75 m s- 1 (4.7%; p = 0.0045). At these speeds, the metabolically optimal exoskeleton stiffness provided peak assistive torques of ~ 0.20 Nm kg- 1 that resulted in reduced biological ankle moment of ~ 12% and reduced soleus muscle activity of ~ 10%. We found no stiffness that could reduce the metabolic cost of walking at 1.5 m s- 1. Across all speeds, the non-weighted sum of soleus and tibialis anterior activation rate explained the change in metabolic rate due to exoskeleton assistance (p < 0.05; R2 > 0.56). CONCLUSIONS: Elastic ankle exoskeletons with low rotational stiffness reduce users' metabolic cost of walking at slow and fast but not intermediate walking speed. The relationship between the non-weighted sum of soleus and tibialis activation rate and metabolic cost (R2 > 0.56) indicates that muscle activation may drive metabolic demand. Future work using simulations and ultrasound imaging will get 'under the skin' and examine the interaction between exoskeleton stiffness and plantarflexor muscle dynamics to better inform stiffness selection in human-machine systems.

The exoskeleton expansion: improving walking and running economy.

Since the early 2000s, researchers have been trying to develop lower-limb exoskeletons that augment human mobility by reducing the metabolic cost of walking and running versus without a device. In 2013, researchers finally broke this 'metabolic cost barrier'. We analyzed the literature through December 2019, and identified 23 studies that demonstrate exoskeleton designs that improved human walking and running economy beyond capable without a device. Here, we reviewed these studies and highlighted key innovations and techniques that enabled these devices to surpass the metabolic cost barrier and steadily improve user walking and running economy from 2013 to nearly 2020. These studies include, physiologically-informed targeting of lower-limb joints; use of off-board actuators to rapidly prototype exoskeleton controllers; mechatronic designs of both active and passive systems; and a renewed focus on human-exoskeleton interface design. Lastly, we highlight emerging trends that we anticipate will further augment wearable-device performance and pose the next grand challenges facing exoskeleton technology for augmenting human mobility.

Older Adults Overcome Reduced Triceps Surae Structural Stiffness to Preserve Ankle Joint Quasi-Stiffness During Walking.

Ankle joint quasi-stiffness is an aggregate measure of the interaction between triceps surae muscle stiffness and Achilles tendon stiffness. This interaction may be altered due to age-related changes in the structural properties and functional behavior of the Achilles tendon and triceps surae muscles. The authors hypothesized that, due to a more compliant of Achilles' tendon, older adults would exhibit lower ankle joint quasi-stiffness than young adults during walking and during isolated contractions at matched triceps surae muscle activations. The authors also hypothesized that, independent of age, triceps surae muscle stiffness and ankle joint quasi-stiffness would increase with triceps surae muscle activation. The authors used conventional gait analysis in one experiment and, in another, electromyographic biofeedback and in vivo ultrasound imaging applied during isolated contractions. The authors found no difference in ankle joint quasi-stiffness between young and older adults during walking. Conversely, this study found that (1) young and older adults modulated ankle joint quasi-stiffness via activation-dependent changes in triceps surae muscle length-tension behavior and (2) at matched activation, older adults exhibited lower ankle joint quasi-stiffness than young adults. Despite age-related reductions during isolated contractions, ankle joint quasi-stiffness was maintained in older adults during walking, which may be governed via activation-mediated increases in muscle stiffness.

Caregiver Burden Due to Pulmonary Exacerbations in Patients with Cystic Fibrosis.

OBJECTIVE: To describe the poorly understood burden of pulmonary exacerbations experienced by primary caregivers of children (aged 2-17 years) with cystic fibrosis (CF), who frequently require prolonged hospitalizations for treatment of pulmonary exacerbations with intravenous (IV) antibiotics. STUDY DESIGN: In this prospective observational study, 88 caregivers in Germany, Ireland, the United Kingdom, and the US completed a survey during pulmonary exacerbation-related hospitalizations (T1) and after return to a "well state" of health (T2). The impact of pulmonary exacerbations on caregiver-reported productivity, mental/physical health, and social/family/emotional functioning was quantified. RESULTS: Primary caregivers of children with CF reported significantly increased burden during pulmonary exacerbations, as measured by the 12-item Short-Form Health Survey mental health component and the Work Productivity and Activity Impairment: Specific Health Problem absenteeism, presenteeism, work productivity loss, and activity impairment component scores. Compared to the "well state," during pulmonary exacerbations-related hospitalization caregivers reported lower physical health scores on the Child Health Questionnaire-Parent Form 28. Quality-of-life scores on the Caregiver Quality of Life Cystic Fibrosis scale and total support score on the Multidimensional Scale of Perceived Social Support did not differ significantly between T1 and T2. More caregivers reported a negative impact on family/social/emotional functioning during pulmonary exacerbations than during the "well state." CONCLUSIONS: Pulmonary exacerbations necessitating hospitalization impose a significant burden on primary caregivers of children with CF. Preventing pulmonary exacerbations may substantially reduce this burden.

Exoskeletons Improve Locomotion Economy by Reducing Active Muscle Volume.

Exoskeletons that improve locomotion economy typically are engineered to reduce users' limb joint mechanical work or moments. Yet, limb joint dynamics do not necessarily reflect muscle dynamics, which dictate whole-body metabolic energy expenditure. Here, we hypothesize that exoskeletons primarily reduce user metabolic energy expenditure across locomotion conditions by reducing active muscle volume.

Disparities in Mortality of Hispanic Patients with Cystic Fibrosis in the United States. A National and Regional Cohort Study.

RATIONALE: Patients of Hispanic origin with cystic fibrosis (CF) are the largest growing minority, representing 8.5% of patients with CF in the United States. No national survival analysis of this group has ever been undertaken. OBJECTIVES: We aimed to determine whether Hispanic ethnicity within the CF population is associated with worse outcomes and whether any geographic differences exist. METHODS: Using U.S. Cystic Fibrosis Foundation Patient Registry data from 2010 to 2014, we performed a retrospective cohort analysis comparing survival rates between Hispanics and non-Hispanics using Kaplan-Meier and Cox regression analysis. A subject's residence was categorized into geographic regions based on U.S. Census Bureau data: Northeast, Midwest, West, and South. MEASUREMENTS AND MAIN RESULTS: A total of 29,637 patients were included in the study; 2,493 identified themselves as Hispanic. Hispanics had a lower survival probability overall, with a mean age of death of 22.4 ± 9.9 years compared with non-Hispanics of 28.1 ± 10.0 years (P < 0.0001). Multivariate Cox proportional hazards modeling revealed that Hispanic patients with CF had a 1.27 times higher rate of death compared with non-Hispanics (95% confidence interval, 1.05-1.53) after adjusting for covariates including age, sex, genetic mutations, bacterial cultures, lung function, body mass index, use of CF respiratory therapies, low socioeconomic status, pancreatic enzyme use, and CF-related diabetes. When analyzed by region, Hispanics in the Midwest, Northeast, and West had shorter median survivals compared with non-Hispanics, which was not demonstrated in the South. CONCLUSIONS: Patients with CF of Hispanic origin have a higher mortality rate than non-Hispanic patients with CF. This pattern was seen in the Midwest, Northeast, and West but not in the South.

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.

Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor.

BACKGROUND: Ivacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers. OBJECTIVE: This ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability. METHODS: Annual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here. RESULTS: Analyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function. CONCLUSIONS: While general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor. EU PAS REGISTRATION NUMBER: EUPAS4270.

Utilization of a patient-centered asthma passport tool in a subspecialty clinic.

INTRODUCTION: Despite available and effective tools for asthma self-assessment (Asthma Control Test, ACT) and self-management (Asthma Action Plan, AAP), they are underutilized in outpatient specialty clinics. We evaluated the impact of a patient-centered checklist, the Asthma Passport, on improving ACT and AAP utilization in clinic. METHODS: This was a randomized, interventional quality-improvement project in which the Asthma Passport was distributed to 120 pediatric asthma patients over the duration of 16 weeks. The passport's checklist consisted of tasks to be completed by the patient/family, including completion of the ACT and AAP. We compared rates of completion of the ACT and AAP for those who received the passport versus the control group, and assessed patient/caregiver and provider satisfaction. RESULTS: Based on electronic medical record data from 222 participants, the ACT completion rate was not significantly different between the passport and control groups, however, the AAP completion rate was significantly greater than control (30.0% vs. 17.7%, p = 0.04). When per-protocol analysis was limited to groups who completed and returned their passports, ACT and AAP completion rates were significantly greater than control (73.8% vs. 44.1% (p = 0.002) and 35.7% vs. 17.7% (p = 0.04), respectively). Nearly all participants reported high satisfaction with care, and surveyed providers viewed the passport favorably. CONCLUSIONS: A patient-centered checklist significantly improved the completion rate of the AAP. For patient's who completed and returned the asthma passport, the ACT completion rate was also improved. Participants and providers reported high satisfaction with the checklist, suggesting that it can effectively promote asthma self-management and self-assessment without burdening clinicians or clinic workflow.

Unconstrained muscle-tendon workloops indicate resonance tuning as a mechanism for elastic limb behavior during terrestrial locomotion.

In terrestrial locomotion, there is a missing link between observed spring-like limb mechanics and the physiological systems driving their emergence. Previous modeling and experimental studies of bouncing gait (e.g., walking, running, hopping) identified muscle-tendon interactions that cycle large amounts of energy in series tendon as a source of elastic limb behavior. The neural, biomechanical, and environmental origins of these tuned mechanics, however, have remained elusive. To examine the dynamic interplay between these factors, we developed an experimental platform comprised of a feedback-controlled servo-motor coupled to a biological muscle-tendon. Our novel motor controller mimicked in vivo inertial/gravitational loading experienced by muscles during terrestrial locomotion, and rhythmic patterns of muscle activation were applied via stimulation of intact nerve. This approach was based on classical workloop studies, but avoided predetermined patterns of muscle strain and activation-constraints not imposed during real-world locomotion. Our unconstrained approach to position control allowed observation of emergent muscle-tendon mechanics resulting from dynamic interaction of neural control, active muscle, and system material/inertial properties. This study demonstrated that, despite the complex nonlinear nature of musculotendon systems, cyclic muscle contractions at the passive natural frequency of the underlying biomechanical system yielded maximal forces and fractions of mechanical work recovered from previously stored elastic energy in series-compliant tissues. By matching movement frequency to the natural frequency of the passive biomechanical system (i.e., resonance tuning), muscle-tendon interactions resulting in spring-like behavior emerged naturally, without closed-loop neural control. This conceptual framework may explain the basis for elastic limb behavior during terrestrial locomotion.