One challenge for synthetic biologists is the predictable tuning of genetic circuit regulatory components to elicit desired outputs. Gene expression driven by ligand-inducible transcription factor ...systems must exhibit the correct ON and OFF characteristics: appropriate activation and leakiness in the presence and absence of inducer, respectively. However, the dynamic range of a promoter (i.e., absolute difference between ON and OFF states) is difficult to control. We report a method that tunes the dynamic range of ligand-inducible promoters to achieve desired ON and OFF characteristics. We build combinatorial sets of AraC-and LasR-regulated promoters containing -10 and -35 sites from synthetic and Escherichia coli promoters. Four sequence combinations with diverse dynamic ranges were chosen to build multi-input transcriptional logic gates regulated by two and three ligand-inducible transcription factors (LacI, TetR, AraC, XylS, RhlR, LasR, and LuxR). This work enables predictable control over the dynamic range of regulatory components.
The standard functional tool for gait assessment in multiple sclerosis (MS) clinical trials has been the 25-Foot Timed Walk Test, a measure of gait speed. Straight-line gait assessment may not ...reflect adequately upon balance and coordination. Walking tests with turns may add additional information towards understanding gait and balance status, and be more reflective of ambulation in the community. Understanding the impact of turn parameters on patient-reported outcomes of balance and walking would help MS clinicians better formulate treatment plans for persons with gait limitations. In this study, ninety-one persons with MS (Expanded Disability Status Score; EDSS, range: 0-6.5) were enrolled in an initial cross-sectional study. Twenty-four subjects (EDSS, range:1.0-6.0) completed a follow-up visit an average of 12 months later. Spatiotemporal gait analysis was collected at both visits using APDM Opal wireless body-worn sensors while performing the Timed-Up-and-Go (TUG) and 6-Minute Walk Test (6MWT). For both cross-sectional and longitudinal data, regression analyses determined the impact on the addition of turning parameters to stride velocity (SV), in the prediction of self-reported balance confidence (Activities-Specific Balance Confidence Scale (ABC)) and walking limitation (12-item Multiple Sclerosis Walking Scale (MSWS-12)). The addition of 6MWT peak turn velocity (PTV) to 6MWT SV increased the predictive power of the 6MWT for the ABC from 20% to 33%, and increased the predictive power from 28% to 41% for the MSWS-12. TUG PTV added to TUG SV also strengthened the relationship of the TUG for the ABC from 19% to 28%, and 27% to 36% for the MSWS-12. For those with 1 year follow-up, percent change in turn number of steps (TNS%Δ) during the 6MWT added to 6MWT SV%Δ improved the modeling of ABC%Δ from 24% to 33%. 6MWT PTV%Δ added to 6MWT SV%Δ increased the predictive power of MSWS-12%Δ from 8% to 27%. Conclusively, turn parameters improved modeling of self-perceived balance confidence and walking limitations when added to the commonly utilized measure of gait speed. Tests of longer durations with multiple turns, as opposed to shorter durations with a single turn, modeled longitudinal change more accurately. Turn speed and stability should be qualitatively assessed during the clinic visit, and use of multi-faceted tests such as the TUG or 6MWT may be required to fully understand gait deterioration in persons with MS.
Three-dimensional kinematic analysis of reaching has emerged as an evaluative measure of upper-extremity motor performance in people after stroke. However, the psychometric properties supporting the ...use of kinematic data for evaluating longitudinal change in motor performance have not been established. The objective of this study was to determine, in a test-retest reliability manner, the reproducibility and minimal detectable change for reaching kinematics in people after stroke.
Fourteen participants with hemiparesis after stroke performed forward reaching tasks on 2 occasions 37.3 (SD=9.8) days apart. At each session, participants performed 4 forward reaching tasks produced by the combination of 2 target heights (low and high 109 and 153 cm from the floor, respectively) and 2 instructed movement speeds (self-selected and as fast as possible). Two analytical methods were used to calculate kinematic parameters.
Relative reliability (intraclass correlation coefficient) ranged from .04 to .99, and absolute reliability (standard error of measurement) ranged from 2.7% to 76.8%, depending on the kinematic variable, the demands of the motor task (target height and movement speed), and the analytical method. Bland-Altman analysis, a statistical method used to assess the repeatability of a method, revealed few systematic errors between sessions. The minimal detectable change ranged from 7.4% to 98.9%.
Depending on the demands of the motor task and the analytical method, most kinematic outcome measures (such as peak hand velocity, endpoint error, reach extent, maximum shoulder flexion range of motion, and minimum elbow extension range of motion) are reliable measures of motor performance in people after stroke. However, because of the magnitude of within-subject measurement error, some variables (such as peak hand velocity, time to peak hand velocity, and movement time) must change considerably (>50%) to indicate a real change in individual participants. The results of our reliability analysis, which are based on our cohort of participants with hemiparesis after stroke and our specific paradigm, may not be generalizable to different subpopulations of people with hemiparesis after stroke or to the myriad movement tasks and kinematic variables used for the assessment of reaching performance in people after stroke.
Gait impairments in persons with multiple sclerosis (pwMS) leading to decreased ambulation and reduced walking endurance remain poorly understood. Our objective was to assess gait asymmetry (GA) and ...bilateral coordination of gait (BCG), among pwMS during the six-minute walk test (6MWT), and determine their association with disease severity. We recruited 92 pwMS (age: 46.6 ± 7.9; 83% females) with a range of clinical disability, who completed the 6MWT wearing gait analysis system. GA was assessed by comparing left and right swing times, and BCG was assessed by the phase coordination index (PCI). Several functional and subjective gait assessments were performed. Results show that gait is more asymmetric and less coordinated as the disease progresses (p < 0.0001). Participants with mild MS showed significantly better BCG as reflected by lower PCI values in comparison to the other two MS severity groups (severe: p = 0.001, moderate: p = 0.02). GA and PCI also deteriorated significantly each minute during the 6MWT (p < 0.0001). GA and PCI (i.e., BCG) show weaker associations with clinical MS status than associations observed between functional and subjective gait assessments and MS status. Similar to other neurological cohorts, GA and PCI may be important parameters to assess and target in interventions among pwMS.
Diphtheria incidence has decreased in Europe since its resurgence in the 1990s, but circulation continues in some countries in eastern Europe, and sporadic cases have been reported elsewhere. ...Surveillance data from Diphtheria Surveillance Network countries and the World Health Organization European Region for 2000-2009 were analyzed. Latvia reported the highest annual incidence in Europe each year, but the Russian Federation and Ukraine accounted for 83% of all cases. Over the past 10 years, diphtheria incidence has decreased by >95% across the region. Although most deaths occurred in disease-endemic countries, case-fatality rates were highest in countries to which diphtheria is not endemic, where unfamiliarity can lead to delays in diagnosis and treatment. In western Europe, toxigenic Corynebacterium ulcerans has increasingly been identified as the etiologic agent. Reduction in diphtheria incidence over the past 10 years is encouraging, but maintaining high vaccination coverage is essential to prevent indigenous C. ulcerans and reemergence of C. diphtheriae.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by episodic decline in various neurologic functions. Gait dysfunction in MS is distinguished by ...decreased gait speed, walking endurance, step length, cadence and joint motion, as well as increased metabolic cost of walking and increased variability of gait. Standardized clinical, timed, and patient-based measures can identify MS patients with gait dysfunction, and observational gait analysis, instrumented walkways, or three-dimensional gait analysis can help determine which problem underlies their gait dysfunction to help direct effective treatment. Exercise may ameliorate all types of gait dysfunction. In addition, gait dysfunction due to weakness may be alleviated by orthoses or functional electrical stimulation; gait dysfunction due to spasticity may be relieved by oral, intrathecal, or intramuscular medications. Assistive devices and balance training may reduce gait dysfunction from imbalance, and dalfampridine may accelerate gait in people with MS who walk slowly.
To determine whether plantarflexor (PF) spasticity or ankle strength best predicts variance in walking capacity or self-perceived limitations in walking in persons with multiple sclerosis (MS) and ...whether persons with MS with PF spasticity are weaker and have greater walking dysfunction than do persons with MS without PF spasticity.
Cross-sectional study.
University research laboratory.
Forty-two adults with MS (mean age, 42.9±10.1y; Expanded Disability Status Scale score, median=3.0, range=0-6) and 14 adults without disability (mean age, 41.9±10.1y).
Not applicable.
PF spasticity and dorsiflexion and PF maximum voluntary isometric torque were assessed using the modified Ashworth Scale and a computerized dynamometer, respectively. The Timed 25-Foot Walk Test was the primary outcome measure of walking capacity. Secondary measures included the 6-Minute Walk Test and the 12-item Multiple Sclerosis Walking Scale.
PF strength was the most consistent predictor of variance in walking capacity (Timed 25-Foot Walk Test: R(2) change=.23-.29, P≤.001; 6-Minute Walk Test: R(2) change=.12-.29, P≤.012), and self-perceived limitations of walking (12-item Multiple Sclerosis Walking Scale: R(2) change=.04-.14, P<.18). There were no significant differences (P>.05) between persons with MS with PF spasticity and persons with MS without PF spasticity for any of the outcome measures.
Our study suggests a unique contribution of PF weakness to walking dysfunction in persons with MS, and highlights the importance of evaluating PF strength in this clinical population.
Many people with multiple sclerosis (MS) have spasticity, generally in the lower limbs, but this symptom is complex and multidimensional and therefore difficult to characterize.
MS spasticity may be ...influenced by moderators, triggers, modifiers, and treatment, all of which can affect objective measures and the subjective experience of spasticity.
MS spasticity can have physical, functional, social, and emotional/psychological impacts as well as long-term consequences that can affect rehabilitation and ultimately reduce health-related quality of life for people with MS.
Given that people with MS may view spasticity differently than their rehabilitation providers, providers should ask patients about their spasticity, including their moderators, triggers, modifiers, experience, impacts, long-term consequences, and effects on quality of life.
This conceptual model provides a framework to improve clinician-patient dialogue, research, and rehabilitation for MS spasticity.
Spasticity is common in multiple sclerosis (MS), often leading to functional limitations and disability. We developed a conceptual model of spasticity in MS integrating expert opinion, recent literature, and experiences of clinicians and people with MS spasticity.
A conceptual model was developed based on a targeted literature review of articles published between 2014 and 2019, followed by input from clinicians, then input from participants with MS spasticity. Multidisciplinary experts on spasticity provided guidance at each step.
Key concepts of the integrated spasticity conceptual model included: moderators; triggers; modifiers; treatment; objective manifestations; subjective experience; physical, functional, social, and emotional/psychological impacts; and long-term consequences. Participants with MS spasticity most frequently endorsed spasms, tightness, and pain as descriptors of spasticity. Some participants with MS spasticity had difficulty distinguishing spasticity from other MS symptoms (e.g. muscle weakness). Some triggers, emotional/psychological impacts, and long-term consequences of spasticity reported by participants with MS spasticity were not previously identified in the published literature.
This conceptual model of spasticity, integrating published literature with the experience of clinicians, people with MS spasticity, and experts, demonstrates the complex, multidimensional nature of MS spasticity. This model may be used to improve clinician-patient dialogue, research, and patient care.
To examine the responsiveness and validity of the Action Research Arm Test (ARAT) in a population of subjects with mild-to-moderate hemiparesis within the first few months after stroke.
Data were ...collected as part of the Very Early Constraint-Induced Therapy for Recovery from Stroke trial, an acute, single-blind randomized controlled trial of constraint-induced movement therapy. Subjects were studied at baseline (day 0), after treatment (day 14), and after 90 days (day 90) poststroke.
Inpatient rehabilitation hospital; follow-up 3 months poststroke.
Fifty hemiparetic subjects.
Not applicable.
At each time point, subjects were tested on: (1) the ARAT, (2) clinical measures of sensorimotor impairments, (3) in the kinematics laboratory where they performed reach and grasp movements, and (4) clinical measures of disability. Blinded raters performed all evaluations. Analyses at each time point included calculating effect size as indicators of responsiveness, and correlation and regression analyses to examine relationships between ARAT scores and other measures.
The ARAT is responsive to change, with effect sizes greater than 1.0 and responsiveness ratios of 7.0 at 3 months poststroke. ARAT scores were related to sensorimotor impairment measures, 3-dimensional kinematic measures of movement performance, and disability measures at all 3 time points.
The ARAT is a responsive and valid measure of upper-extremity functional limitation and therefore may be an appropriate measure for use in acute upper-extremity rehabilitation trials.
This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts.
...This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex.
Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p < 0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p < 0.0001). 25FTW was associated with RD and FA in PCs (p < 0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p < 0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI.
DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.
PDF
