Comparison of a computerized algorithm and prosthetists' judgment in rating functional levels based on daily step activity in transtibial amputees.

The Medicare Functional Classification Levels: "K-Level" system is a standard scale for functional levels of amputees. But it is problematic to document objectively and reliably. The K-Levels are based on three characteristics: potential to ambulate, cadence variability and energy level of the amputees. Actual mobility patterns of transtibial amputees recorded by a step activity monitor (StepWatch™) were translated using a computerized algorithm to match the three K-Level characteristics: the most active one minute, the ratio of low:medium:high step rates, and the total daily steps, respectively. This study compared prosthetists' ratings of functional levels based on a visual inspection of step activity patterns with the ratings calculated by the computerized algorithm based on the same step activity data in 81 transtibial amputees. The computerized algorithm produced functional level values that closely matched the average of the ratings by 14 experienced prosthetists. The slope of the linear regression line was 1.04 with an R 2 value of 0.829, indicating good linearity and concordance across the range of the two scales. The results of this study demonstrated concurrent validity of the computerized algorithm and suggested that it could potentially serve as a useful tool in rating functional levels of transtibial amputees based on real-world step activities and complement a clinic-based test.

Mental health first aid training for nursing students: a protocol for a pragmatic randomised controlled trial in a large university.

BACKGROUND: The impact of mental health problems and disorders in Australia is significant. Mental health problems often start early and disproportionately affect young people. Poor adolescent mental health can predict educational achievement at school and educational and occupational attainment in adulthood. Many young people attend higher education and have been found to experience a range of mental health issues. The university setting therefore presents a unique opportunity to trial interventions to reduce the burden of mental health problems. Mental Health First Aid (MHFA) aims to train participants to recognise symptoms of mental health problems and assist an individual who may be experiencing a mental health crisis. Training nursing students in MHFA may increase mental health literacy and decrease stigma in the student population. This paper presents a protocol for a trial to examine the efficacy of the MHFA training for students studying nursing at a large university in Perth, Western Australia. METHODS/DESIGN: This randomised controlled trial will follow the CONSORT guidelines. Participants will be randomly allocated to the intervention group (receiving a MHFA training course comprising two face to face 6.5 hour sessions run over two days during the intervention period) or a waitlisted control group (not receiving MHFA training during the study). The source population will be undergraduate nursing students at a large university located in Perth, Western Australia. Efficacy of the MHFA training will be assessed by following the intention-to-treat principle and repeated measures analysis. DISCUSSION: Given the known burden of mental health disorders among student populations, it is important universities consider effective strategies to address mental health issues. Providing MHFA training to students offers the advantage of increasing mental health literacy, among the student population. Further, students trained in MHFA are likely to utilise these skills in the broader community, when they graduate to the workforce. It is anticipated that this trial will demonstrate the scalability of MHFA in the university environment for pre-service nurses and that implementation of MHFA courses, with comprehensive evaluation, could yield positive improvements in the mental health literacy amongst this target group as well as other tertiary student groups. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000861651 .

Ataluren treatment of patients with nonsense mutation dystrophinopathy.

INTRODUCTION: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. METHODS: Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. RESULTS: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. CONCLUSIONS: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.

Influence of malalignment on socket reaction moments during gait in amputees with transtibial prostheses.

Alignment - the process and measured orientation of the prosthetic socket relative to the foot - is important for proper function of a transtibial prosthesis. Prosthetic alignment is performed by prosthetists using visual gait observation and amputees' feedback. The aim of this study was to investigate the effect of transtibial prosthesis malalignment on the moments measured at the base of the socket: the socket reaction moments. Eleven subjects with transtibial amputation were recruited from the community. An instrumented prosthesis alignment component was used to measure socket reaction moments during ambulation under 17 alignment conditions, including nominally aligned using conventional clinical methods, and angle perturbations of 3° and 6° (flexion, extension, abduction, and adduction) and translation perturbations of 5mm and 10mm (anterior, posterior, lateral, and medial) referenced from the nominal alignment. Coronal alignment perturbations caused systematic changes in the coronal socket reaction moments. All angle and translation perturbations revealed statistically significant differences on coronal socket reaction moments compared to the nominal alignment at 30% and 75% of stance phase (P<0.05). The effect of sagittal alignment perturbations on sagittal socket reaction moments was not as responsive as that of the coronal perturbations. The sagittal angle and translation perturbations of the socket led to statistically significant changes in minimum moment, maximum moment, and moments at 45% of stance phase in the sagittal plane. Therefore, malalignment affected the socket reaction moments in amputees with transtibial prostheses.

Perception of socket alignment perturbations in amputees with transtibial prostheses.

A person with amputation's subjective perception is the only tool available to describe fit and comfort to a prosthetist. However, few studies have investigated the effect of alignment on this perception. The aim of this article is to determine whether people with amputation could perceive the alignment perturbations of their prostheses and effectively communicate them. A randomized controlled perturbation of angular (3 and 6 degrees) and translational (5 and 10 mm) alignments in the sagittal (flexion, extension, and anterior and posterior translations) and coronal (abduction, adduction, and medial and lateral translations) planes were induced from an aligned condition in 11 subjects with transtibial prostheses. The perception was evaluated when standing (static) and immediately after walking (dynamic) using software that used a visual analog scale under each alignment condition. In the coronal plane, Friedman test demonstrated general statistical differences in static (p < 0.001) and dynamic (p < 0.001) measures of perceptions with angular perturbations. In the sagittal plane, it also demonstrated general statistical differences in late-stance dynamic measures of perceptions (p < 0.001) with angular perturbations, as well as in early-stance dynamic measures of perceptions (p < 0.05) with translational perturbations. Fisher exact test suggested that people with amputation's perceptions were good indicators for coronal angle malalignments but less reliable when defining other alignment conditions.

Walking stride rate patterns in children and youth.

PURPOSE: To describe walking activity patterns in youth who are typically developing (TD) using a novel analysis of stride data and compare to youth with cerebral palsy (CP) and arthrogryposis (AR). METHOD: Stride rate curves were developed from 5 days of StepWatch data for 428 youth ages 2 to 16 years who were TD. RESULTS: Patterns of stride rates changed with age in the TD group (P = .03 to < .001). Inactivity varied with age (P < .001); peak stride rate decreased with age (P < .001). Curves were stable over a 2-week time frame (P = .38 to .95). Youth with CP and AR have lower stride rate patterns (P = .04 to .001). CONCLUSION: This is the first documentation of pediatric stride-rate patterns within the context of daily life. Including peak stride rates and levels of walking activity, this single visual format has potential clinical and research applications.

Validation of the StepWatch device for measurement of free-living ambulatory activity in patients with chronic obstructive pulmonary disease.

This study examined the validity of the StepWatch activity monitor and the optimal number of monitoring days in patients with chronic obstructive pulmonary disease (COPD). StepWatch activity data were obtained from databases of two studies: one of patients with COPD who participated in a trial of two exercise persistence interventions (n = 17) and a second, cross-sectional study of activity in chronically healthy older adults (n = 60). Independent t tests, Pearson's correlations, and Bland-Altman plots were used to examine the activity data (total steps, activity intensity, and distribution of activity). Results indicated that patients with COPD registered 50% fewer total steps and had lower levels of walking intensity compared with chronically healthy older adults. Activity parameters had moderate-to-high correlations with disease severity, peak cycle workload, and physical functioning. More monitoring days were associated with greater measurement precision. This study provides preliminary evidence to support the validity of the StepWatch device for measuring free-living ambulatory physical activity in COPD.

Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth.

17q11 microdeletions that encompass NF1 cause 5%-10% of cases of neurofibromatosis type 1, and individuals with microdeletions are typically taller than individuals with intragenic NF1 mutations, suggesting that deletion of a neighboring gene might promote human growth. We identified mutations in RNF135, which is within the NF1 microdeletion region, in six families characterized by overgrowth, learning disability, dysmorphic features and variable additional features. These data identify RNF135 as causative of a new overgrowth syndrome and demonstrate that RNF135 haploinsufficiency contributes to the phenotype of NF1 microdeletion cases.

Using step activity monitoring to characterize ambulatory activity in community-dwelling older adults.

OBJECTIVES: To explore the potential of using step activity monitoring to detect differences in ambulatory activity associated with advancing age and declining function in community-dwelling seniors. DESIGN: Cross-sectional pilot study. SETTING: General communities of Seattle, Washington; Catonsville, Maryland; and Durham, North Carolina. PARTICIPANTS: Thirty healthy younger adults, 28 healthy older adults, and 12 older adults reporting functional limitations. MEASUREMENTS: Ambulatory activity data were collected over 6 days with the StepWatch 3. Average daily values were calculated for number of steps, number of minutes of activity, number of activity bouts, variability of minute-to-minute activity, and randomness of minute-to-minute activity fluctuations. RESULTS: Healthy older adults engaged in fewer bouts of activity (P=.03) and displayed less-variable activity (P=.02) than younger adults. Older adults reporting functional limitations not only engaged in fewer bouts of activity (P=.009) and less variable activity (P<.001) than younger adults, but also accumulated fewer total steps (P=.003) and minutes of activity (P=.008) and had less-random minute-to-minute activity fluctuations (P=.02). CONCLUSION: Step activity monitoring data were useful for detecting differences in ambulatory activity according to age and functional limitation. Monitor-based measures reflecting patterns of ambulatory activity show promise for use in studies of physical functioning.

Use of the StepWatch activity monitor for characterization of normal activity levels of children.

Clinical and research measures for walking activity measure capacity and performance. Existing tools such as 3-dimensional gait analysis and validated gross motor instruments examine capacity but do not measure performance. We defined normal activity levels for 20 children ages 5-7 and 9-11 years using the StepWatch Activity Monitor (SAM). Average daily step counts varied widely by age and sex (mean 7604 +/- 2485), but the percent time spent at high, medium, and low levels of activity was very consistent regardless of age or sex of the child.

Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome.

We previously demonstrated that constitutional BUB1B mutations cause mosaic variegated aneuploidy, a condition characterized by constitutional aneuploidies and childhood cancer predisposition. To further investigate the role of BUB1B in cancer predisposition we performed comparative genomic hybridization analysis in an embryonal rhabdomyosarcoma from an MVA case with biallelic BUB1B mutations, revealing aneuploidies typical of sporadic E-RMS, with gain of chromosomes 3, 8, 13 and loss of chromosomes 9, 14, X. To investigate whether somatic BUB1B mutations occur in sporadic childhood cancers we screened 30 Wilms tumours, 10 acute lymphoblastic leukemias, nine rhabdomyosarcomas and 11 rhabdomyosarcoma cell lines for BUB1B mutations. We identified seven exonic and six intronic variants. Six of the exonic variants were synonymous and one resulted in a non-synonymous conservative missense alteration that was also present in a control. These data suggest that the genetic progression in rhabdomyosarcoma from MVA and non-MVA cases may be similar, but that somatic BUB1B mutations are unlikely to be common in sporadic childhood cancers known to be associated with MVA.

Familial gigantism caused by an NSD1 mutation.

A three-generation family with autosomal dominant segregation of a novel NSD1 mutation (6605G --> A, resulting in Cys2202Tyr) is reported. Haploinsufficiency of NSD1 has been identified as the major cause of Sotos syndrome. The overgrowth condition (MIM 117550) is characterized by facial anomalies, macrocephaly, advanced bone age, and learning disabilities. Manifestations in the present family include dramatically increased height, weight, and head circumference together with a long face, large mandible, and large ears, but mental deficiency was absent.

Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations.

We identified 266 individuals with intragenic NSD1 mutations or 5q35 microdeletions encompassing NSD1 (referred to as "NSD1-positive individuals"), through analyses of 530 subjects with diverse phenotypes. Truncating NSD1 mutations occurred throughout the gene, but pathogenic missense mutations occurred only in functional domains (P < 2 x 10(-16)). Sotos syndrome was clinically diagnosed in 99% of NSD1-positive individuals, independent of the molecular analyses, indicating that NSD1 aberrations are essentially specific to this condition. Furthermore, our data suggest that 93% of patients who have been clinically diagnosed with Sotos syndrome have identifiable NSD1 abnormalities, of which 83% are intragenic mutations and 10% are 5q35 microdeletions. We reviewed the clinical phenotypes of 239 NSD1-positive individuals. Facial dysmorphism, learning disability, and childhood overgrowth were present in 90% of the individuals. However, both the height and head circumference of 10% of the individuals were within the normal range, indicating that overgrowth is not obligatory for the diagnosis of Sotos syndrome. A broad spectrum of associated clinical features was also present, the occurrence of which was largely independent of genotype, since individuals with identical mutations had different phenotypes. We compared the phenotypes of patients with intragenic NSD1 mutations with those of patients with 5q35 microdeletions. Patients with microdeletions had less-prominent overgrowth (P = .0003) and more-severe learning disability (P = 3 x 10(-9)) than patients with mutations. However, all features present in patients with microdeletions were also observed in patients with mutations, and there was no correlation between deletion size and the clinical phenotype, suggesting that the deletion of additional genes in patients with 5q35 microdeletions has little specific effect on phenotype. We identified only 13 familial cases. The reasons for the low vertical transmission rate are unclear, although familial cases were more likely than nonfamilial cases (P = .005) to carry missense mutations, suggesting that the underlying NSD1 mutational mechanism in Sotos syndrome may influence reproductive fitness.

Evaluation of NSD2 and NSD3 in overgrowth syndromes.

Sotos syndrome is an overgrowth condition predominantly caused by truncating mutations, missense mutations restricted to functional domains, or deletions of NSD1. NSD1 is a member of a protein family that includes NSD2 and NSD3, both of which show 70-75% sequence identity with NSD1. This strong sequence similarity suggests that abrogation of NSD2 or NSD3 function may cause non-NSD1 Sotos cases or other overgrowth phenotypes. To evaluate this hypothesis, we mutationally screened NSD2 and NSD3 in 78 overgrowth syndrome cases in which NSD1 mutations and deletions had been excluded. Additionally, we used microsatellite markers within the vicinity of the genes to look for whole gene deletions. No truncating mutations or gene deletions were identified in either gene. We identified two conservative missense NSD2 alterations in two non-Sotos overgrowth cases but neither was within a functional domain. We identified three synonymous and two intronic variants in NSD2 and two synonymous base substitutions in NSD3. Our results suggest that despite strong sequence similarity between NSD1, NSD2 and NSD3, the latter genes are unlikely to be making a substantial contribution to overgrowth phenotypes and thus may operate in distinct functional pathways from NSD1.

Accelerometer monitoring of home- and community-based ambulatory activity after stroke.

OBJECTIVES: To investigate the utility of a novel microprocessor-linked Step Watch Activity Monitor (SAM) to quantify ambulatory activity after stroke and to evaluate the validity and reliability of conventional accelerometers to measure free-living physical activity in this population. DESIGN: Cross-sectional with repeated measures of 2 separate 48-hour recordings in 17 persons wearing an ankle-mounted SAM and Caltrac, a hip-mounted mechanical accelerometer. SETTING: Home and community. PARTICIPANTS: Seventeen subjects with chronic hemiparetic gait after stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The SAM derived stride counts per day and Caltrac estimated the daily caloric expenditure of physical activity. RESULTS: SAM data revealed that stroke patients had a mean strides per day +/- standard deviation of 3035+/-1944 and demonstrated a broad range of daily activity profiles (400-6472 strides). SAM test-retest reliability was high across separate monitoring periods (r=.96, P<.001). Although Caltrac also revealed a broad range of daily activity calories (346+/-217 kcal/d; range, 83-1222 kcal/d), reliability was poor (r=.044, P=not significant) and Caltrac accounted for only 64% of the ambulatory activity quantified by the SAM. CONCLUSIONS: Microprocessor-linked accelerometer monitoring, but not conventional accelerometers, are accurate and highly reliable for quantifying ambulatory activity levels in stroke patients. These findings support the utility of personal status monitoring of ambulatory activity as an outcomes instrument and metric in programs to increase physical activity and cardiovascular health after stroke.

Ambulatory activity in men with diabetes: relationship between self-reported and real-world performance-based measures.

The measurement of physical activity, especially walking activity, is important for many outcome studies. In many investigations, the Physical Activity scale of the short-form-36 (SF-36) health assessment questionnaire is used in lieu of an actual physical measurement of walking. This study determined the relationship between the SF-36 questionnaire and the Step Activity Monitor (SAM), a real-world performance-based tool that counts the actual number of steps taken during daily activities. We studied the physical activity of 57 men with diabetes using step count monitoring and the SF-36 questionnaire. The subjects averaged 3,293 steps/day, but had a very wide range (111-11,654) and a large standard deviation (SD = 2,037). The correlations between total daily steps and the SF-36 Physical Component Summary score, and the Physical Function, Bodily Pain, and Vitality scales of the SF-36 were only fair (Pearson's r = 0.376, 0.488, 0.332, 0.380, respectively). The corresponding coefficients of determination range from only 7.7% to 23.8%. Physical activity is a complex concept not completely represented by either the SF-36 or the step counts. The correlation between actual walking activity and the SF-36 is not as strong as many researchers believe. Caution should be exercised with the use of the SF-36 to specifically measure walking activity.

Quantification of prosthetic outcomes: elastomeric gel liner with locking pin suspension versus polyethylene foam liner with neoprene sleeve suspension.

For this randomized crossover trial, we compared two common transtibial socket suspension systems: the Alpha liner with distal locking pin and the Pe-Lite liner with neoprene suspension sleeve. Our original hypotheses asserted that increased ambulatory activity, wear time, comfort, and satisfaction would be found with the elastomeric suspension system. Thirteen subjects completed the study. Following 2.5-month accommodation to each condition, ambulatory activity was recorded (steps/minute for 2 weeks), and subjects completed three questionnaires specific to prosthesis use and pain: the Prosthesis Evaluation Questionnaire (PEQ), a Brief Pain Inventory (BPI) excerpt, and the Socket Comfort Score (SCS). Upon completion, subjects selected their favored system for continued use. Ten subjects preferred the Pe-Lite and three the Alpha. Subjects spent 82% more time wearing the Pe-Lite and took 83% more steps per day. Ambulatory intensity distribution did not differ between systems. No statistically significant differences were found in questionnaire results. Subject feedback for each system was both positive and negative.

Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B.

Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development.