Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history.

Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic variants and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype in a mouse model of CMT4C, emphasizing the need for natural history studies to inform clinical trial readiness. Data, including both genetic information and clinical characteristics, were compiled from the longitudinal, prospective dataset of the Inherited Neuropathy Consortium, a member of the Rare Diseases Clinical Research Network (INC-RDCRN). The Charcot Marie Tooth Neuropathy Score (CMTNS), Examination Score (CMTES) and the Rasch-weighted CMTES (CMTES-R) were used to describe symptoms, neurological examinations and neurophysiological characteristics. Standardized response means were calculated at yearly intervals and a mixed model for repeated measures was used to estimate the change in CMTES and CMTES-R over time. Fifty-six individuals (59% female), median age 27 years (range 2-67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified, including 34 unique variants, 14 of which have not previously been published. Twenty-eight participants had longitudinal data available. While there was no significant difference in the CMTES in those with protein truncating versus non-protein truncating variants, there were significant differences in the mean ulnar nerve compound muscle action potential amplitude, the mean radial sensory nerve action potential amplitude, and in the prevalence of scoliosis, suggesting the possibility of a milder phenotype in individuals with one or two non-protein-truncating variants. Overall, the mean value of the CMTES was 13, reflecting moderate clinical severity. There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants. The CMTES and CMTES-R appeared moderately responsive to change over extended follow-up, demonstrating a standardized response mean of 0.81 standard deviation units or 0.71 standard deviation units, respectively, over 3 years. Our analysis represents the largest cross-sectional and only longitudinal study to date, of the clinical phenotype of both adults and children with CMT4C. With the promise of upcoming genetic treatments, these data will further define the natural history of the disease and inform study design in preparation for clinical trials.

Reliability and sensitivity of radiographic measures of hip dysplasia in childhood Charcot-Marie-Tooth disease.

BACKGROUND: Hip dysplasia is a lack of femoral head coverage and disruption of hip and acetabular alignment and congruency, with severity ranging from mild subluxation in nascent at-risk hips to complete dislocation. Presentation of hip dysplasia in neuromuscular conditions can be sub-clinical or associated with a limp with or without hip pain, abductor and flexor weakness and reduced hip range of motion. Untreated hip dysplasia leads to early onset osteoarthritis requiring hip arthroplasty in early adulthood. Hip dysplasia occurs in 6-20% of children with Charcot-Marie-Tooth disease, however little is known about the reliability and sensitivity of detection on plain film pelvic radiographs. METHODS: 14 common measures of hip dysplasia on anteroposterior pelvis radiographs were independently assessed by 2 orthopaedic specialists in 30 ambulant children with Charcot-Marie-Tooth disease. Hip health was also categorised based on clinical impression to assess the sensitivity of radiographic measures to identify hip dysplasia status. RESULTS: 8 measures (acetabular index, head width, lateral centre-edge angle, lateral uncoverage, medial joint width, migration percentage, neck shaft angle, triradiate status) exhibited 'excellent' reliability between clinical evaluators. 5 of the 30 patients (17%) were identified as having nascent hip dysplasia. Reliable radiographic measures that significantly distinguished between nascent hip dysplasia and healthy hips were acetabular index, lateral centre edge angle, medial joint width and migration percentage. CONCLUSIONS: We have identified a subset of reliable and sensitive radiographic hip measures in children with Charcot-Marie-Tooth disease to prioritise during hip screening to mitigate the deleterious effects of hip dysplasia, pain and disability in adulthood.

Physical performance of children with longitudinal fibular deficiency (fibular hemimelia).

PURPOSE: Longitudinal fibular deficiency (LFD) is the most common congenital long bone deficiency. This study aimed to objectively assess the physical performance of children and adolescents with LFD compared with unaffected peers, and to examine trends over age for subgroups of the LFD population. METHODS: Differences between children with LFD and unaffected peers were examined with hand-held dynamometry for lower-limb muscle strength, Six-Minute Walk Test, Timed up and down stairs test, Star Excursion Balance Test, and Standing long jump. RESULTS: Thirty-nine children with LFD and 284 unaffected peers participated. Children with LFD performed at a lower level than their unaffected peers, on all measures of physical performance (mean 2.1 z-scores lower, all p < 0.01), except in long jump (p = 0.27). When comparing the performance of children with LFD to their unaffected peers across four age groups, there was a significant between-groups difference on all strength measures, and on the Six-Minute Walk distance, between children with and without LFD. These differences were smallest in young children (3-6 years) and largest in the older children (15-18 years) (all p < 0.01). Children with no lengthening surgery performed better on the Six-Minute Walk Test, covering a greater distance during the test, than those who had surgery (mean difference 83 metres, p < 0.01). There were no significant differences between children who had or had not undergone an amputation. CONCLUSIONS: Children with LFD performed at a significantly lower level than unaffected peers on all measures of physical performance other than jumping. The largest differences were in older children. This paper provides baseline functional data for future interventions in LFD. LEVEL OF EVIDENCE: Cross-sectional study.Implications for RehabilitationThis paper provides the first baseline functional data using validated objective measures on a consecutive cohort of children and adolescents with longitudinal fibular deficiency.Children with LFD performed significantly worse than their unaffected peers on all measures of physical performance other than jumping, with children falling further behind their peers as they age.Children who undergo an amputation typically have the most severe anatomical presentation and yet perform at an equivalent functional level.This paper identifies multiple modifiable impairments that represent potential opportunities for rehabilitation professionals to target with conservative treatment options to improve functional performance.

L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial.

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.

Near Infrared Fluorescence Imaging of Intraperitoneal Ovarian Tumors in Mice Using Erythrocyte-Derived Optical Nanoparticles and Spatially-Modulated Illumination.

Ovarian cancer is the deadliest gynecological cancer. Cytoreductive surgery to remove primary and intraperitoneal tumor deposits remains as the standard therapeutic approach. However, lack of an intraoperative image-guided approach to enable the visualization of all tumors can result in incomplete cytoreduction and recurrence. We engineered nano-sized particles derived from erythrocytes that encapsulate the near infrared (NIR) fluorochrome, indocyanine green, as potential imaging probes for tumor visualization during cytoreductive surgery. Herein, we present the first demonstration of the use of these nanoparticles in conjunction with spatially-modulated illumination (SMI), at spatial frequencies in the range of 0-0.5 mm-1, to fluorescently image intraperitoneal ovarian tumors in mice. Results of our animal studies suggest that the nanoparticles accumulated at higher levels within tumors 24 h post-intraperitoneal injection as compared to various other organs. We demonstrate that, under the imaging specifications reported here, use of these nanoparticles in conjunction with SMI enhances the fluorescence image contrast between intraperitoneal tumors and liver, and between intraperitoneal tumors and spleen by nearly 2.1, and 3.0 times, respectively, at the spatial frequency of 0.2 mm-1 as compared to the contrast values at spatially-uniform (non-modulated) illumination. These results suggest that the combination of erythrocyte-derived NIR nanoparticles and structured illumination provides a promising approach for intraoperative fluorescence imaging of ovarian tumor nodules at enhanced contrast.

Phototheranostics Using Erythrocyte-Based Particles.

There has been a recent increase in the development of delivery systems based on red blood cells (RBCs) for light-mediated imaging and therapeutic applications. These constructs are able to take advantage of the immune evasion properties of the RBC, while the addition of an optical cargo allows the particles to be activated by light for a number of promising applications. Here, we review some of the common fabrication methods to engineer these constructs. We also present some of the current light-based applications with potential for clinical translation, and offer some insight into future directions in this exciting field.

Interventions for congenital talipes equinovarus (clubfoot).

BACKGROUND: Congenital talipes equinovarus (CTEV), also known as clubfoot, is a common congenital orthopaedic condition characterised by an excessively turned-in foot (equinovarus) and high medial longitudinal arch (cavus). If left untreated it can result in long-term disability, deformity and pain. Interventions can be conservative (such as splinting or stretching) or surgical. Different treatments might be effective at different stages: at birth (initial presentation); when initial treatment does not work (resistant presentation); when the initial treatment works but the clubfoot returns (relapse/recurrent presentation); and when there has been no early treatment (neglected presentation). This is an update of a review first published in 2010 and last updated in 2014. OBJECTIVES: To assess the effects of any intervention for any type of CTEV in people of any age. SEARCH METHODS: On 28 May 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL Plus, AMED and Physiotherapy Evidence Database. We also searched for ongoing trials in the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov (to May 2019). We checked the references of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating interventions for CTEV, including interventions compared to other interventions, sham intervention or no intervention. Participants were people of all ages with CTEV of either one or both feet. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risks of bias in included trials and extracted the data. We contacted authors of included trials for missing information. We collected adverse event information from trials when it was available. When required we attempted to obtain individual patient data (IPD) from trial authors for re-analysis. If unit-of-analysis issues were present and IPD unavailable we did not report summary data, MAIN RESULTS: We identified 21 trials with 905 participants; seven trials were newly included for this update. Fourteen trials assessed initial cases of CTEV (560 participants), four trials assessed resistant cases (181 participants) and three trials assessed cases of unknown timing (153 participants). The use of different outcome measures prevented pooling of data for meta-analysis, even when interventions and participants were comparable. All trials displayed high or unclear risks of bias in three or more domains. Twenty trials provided data. Two trials reported on the primary outcome of function using a validated scale, but the data were not suitable for inclusion because of unit-of-analysis issues, as raw data were not available for re-analysis. We were able to analyse data on foot alignment (Pirani score), a secondary outcome, from three trials in participants at initial presentation. The Pirani score is a scale ranging from zero to six, where a higher score indicates a more severe foot. At initial presentation, one trial reported that the Ponseti technique significantly improved foot alignment compared to the Kite technique. After 10 weeks of serial casting, the average total Pirani score of the Ponseti group was 1.15 points lower than that of the Kite group (mean difference (MD) -1.15, 95% confidence interval (CI) -1.32 to -0.98; 60 feet; low-certainty evidence). A second trial found the Ponseti technique to be superior to a traditional technique, with mean total Pirani scores of the Ponseti participants 1.50 points lower than after serial casting and Achilles tenotomy (MD -1.50, 95% CI -2.28 to -0.72; 28 participants; very low-certainty evidence). One trial found evidence that there may be no difference between casting materials in the Ponseti technique, with semi-rigid fibreglass producing average total Pirani scores 0.46 points higher than plaster of Paris at the end of serial casting (95% CI -0.07 to 0.99; 30 participants; low-certainty evidence). We found no trials in relapsed or neglected cases of CTEV. A trial in which the type of presentation was not reported showed no evidence of a difference between an accelerated Ponseti and a standard Ponseti treatment in foot alignment. At the end of serial casting, the average total Pirani score in the accelerated group was 0.31 points higher than the standard group (95% CI -0.40 to 1.02; 40 participants; low-certainty evidence). No trial assessed gait using a validated assessment. Health-related quality of life was reported in some trials but data were not available for re-analysis. There is a lack of evidence for the addition of botulinum toxin A during the Ponseti technique, different types of major foot surgery or continuous passive motion treatment following major foot surgery. Most trials did not report on adverse events. Two trials found that further serial casting was more likely to correct relapse after Ponseti treatment than after the Kite technique, which more often required major surgery (risk differences 25% and 50%). In trials evaluating serial casting techniques, adverse events included cast slippage (needing replacement), plaster sores (pressure areas), and skin irritation. Adverse events following surgical procedures included infection and the need for skin grafting. AUTHORS' CONCLUSIONS: From the evidence available, the Ponseti technique may produce significantly better short-term foot alignment compared to the Kite technique. The certainty of evidence is too low for us to draw conclusions about the Ponseti technique compared to a traditional technique. An accelerated Ponseti technique may be as effective as a standard technique, but results are based on a single small comparative trial. When using the Ponseti technique semi-rigid fibreglass casting may be as effective as plaster of Paris. Relapse following the Kite technique more often led to major surgery compared to relapse following the Ponseti technique. We could draw no conclusions from other included trials because of the limited use of validated outcome measures and the unavailability of raw data. Future RCTs should address these issues.

Intravital Vascular Phototheranostics and Real-Time Circulation Dynamics of Micro- and Nanosized Erythrocyte-Derived Carriers.

Erythrocyte-based carriers can serve as theranostic platforms for delivery of imaging and therapeutic payloads. Engineering these carriers at micro- or nanoscales makes them potentially useful for broad clinical applications ranging from vascular diseases to tumor theranostics. Longevity of these carriers in circulation is important in delivering a sufficient amount of their payloads to the target. We have investigated the circulation dynamics of micro (∼4.95 µm diameter) and nano (∼91 nm diameter) erythrocyte-derived carriers in real time using near-infrared fluorescence imaging, and evaluated the effectiveness of such carrier systems in mediating photothermolysis of cutaneous vasculature in mice. Fluorescence emission half-lives of micro- and nanosized carriers in response to a single intravenous injection were ∼49 and ∼15 min, respectively. A single injection of microsized carriers resulted in a 3-fold increase in signal-to-noise ratio that remained nearly persistent over 1 h of imaging time. Our results also suggest that a second injection of the carriers 7 days later can induce a transient inflammatory response, as manifested by the apparent leakage of the carriers into the perivascular tissue. The administration of the carriers into the mice vasculature reduced the threshold laser fluence to induce photothermolysis of blood vessels from >65 to 20 J/cm2. We discuss the importance of membrane physicochemical and mechanical characteristics in engineering erythrocyte-derived carriers and considerations for their clinical translation.

Surgical outcomes of cavovarus foot deformity in children with Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) causes disabling cavovarus foot deformity. Orthopaedic surgery is performed in severe cases; however few studies have investigated whether surgery improves health outcomes during childhood. This study investigated the impact of cavovarus surgery on validated physical, functional, parent/self-reported and biomechanical measures in 21 consecutive patients (mean age at surgery 12.5 years, SD 2.7) evaluated before and after surgery (mean duration 15.7 months, SD 5.9), and compared to natural history data from 206 children with CMT. Measures from the CMT Pediatric Scale evaluated foot alignment (Foot Posture Index), ankle flexibility (lunge test), strength (foot dorsiflexion/plantarflexion by hand-held dynamometry), function (balance, long jump, 6-minute walk test) and self-reported symptoms. Quality of life (Child Health Questionnaire) and gait (pressure loading) were also assessed. Foot Posture Index and lunge improved with surgery by 6.0 points (SD 3.2) and 6.1° (SD 7.3) respectively (p< 0.01), and differed to the natural course of the disease (p< 0.005). Self-reported daily trips/falls reduced from 60% to 13% (p = 0.016). Pressure improved beneath the rearfoot and midfoot (p = 0.043). Surgery had no effect on strength, function or quality of life, which generally mirrored the natural course. Cavovarus surgery improved foot alignment, ankle flexibility and self-reported trips/falls in children with CMT.

Photothermal treatment of port-wine stains using erythrocyte-derived particles doped with indocyanine green: a theoretical study.

Pulsed dye laser irradiation in the wavelength range of 585 to 600 nm is currently the gold standard for treatment of port-wine stains (PWSs). However, this treatment method is often ineffective for deeply seated blood vessels and in individuals with moderate to heavy pigmentation. Use of optical particles doped with the FDA-approved near-infrared (NIR) absorber, indocyanine green (ICG), can potentially provide an effective method to overcome these limitations. Herein, we theoretically investigate the effectiveness of particles derived from erythrocytes, which contain ICG, in mediating photothermal destruction of PWS blood vessels. We refer to these particles as NIR erythrocyte-derived transducers (NETs). Our theoretical model consists of a Monte Carlo algorithm to estimate the volumetric energy deposition, a finite elements approach to solve the heat diffusion equation, and a damage integral based on an Arrhenius relationship to quantify tissue damage. The model geometries include simulated PWS blood vessels as well as actual human PWS blood vessels plexus obtained by the optical coherence tomography. Our simulation results indicate that blood vessels containing micron- or nano-sized NETs and irradiated at 755 nm have higher levels of photothermal damage as compared to blood vessels without NETs irradiated at 585 nm. Blood vessels containing micron-sized NETs also showed higher photothermal damage than blood vessels containing nano-sized NETs. The theoretical model presented can be used in guiding the fabrication of NETs with patient-specific optical properties to allow for personalized treatment based on the depth and size of blood vessels as well as the pigmentation of the individual's skin.

Erythrocyte-Derived Theranostic Nanoplatforms for Near Infrared Fluorescence Imaging and Photodestruction of Tumors.

Nanoparticles activated by near-infrared (NIR) excitation provide a capability for optical imaging and photodestruction of tumors. We have engineered optical nanoconstructs derived from erythrocytes, which are doped with the FDA-approved NIR dye, indocyanine green (ICG). We refer to these constructs as NIR erythrocyte-mimicking transducers (NETs). Herein, we investigate the phototheranostic capabilities of NETs for fluorescence imaging and photodestruction of SKBR3 breast cancer cells and subcutaneous xenograft tumors in mice. Our cellular studies demonstrate that NETs are internalized by these cancer cells and localized to their lysosomes. As evidenced by NIR fluorescence imaging and in vivo laser irradiation studies, NETs remain available within tumors at 24 h postintravenous injection. In response to continuous wave 808 nm laser irradiation at intensity of 680 mW/cm2 for 10-15 min, NETs mediate the destruction of cancer cells and tumors in mice through synergistic photochemical and photothermal effects. We demonstrate that NETs are effective in mediating photoactivation of Caspase-3 to induce tumor apoptosis. Our results provide support for the effectiveness of NETs as theranostic agents for fluorescence imaging and photodestruction of tumors and their role in photoinduced apoptosis initiated by their localization to lysosomes.

Prevalence and orthopedic management of foot and ankle deformities in Charcot-Marie-Tooth disease.

INTRODUCTION: Foot deformities are frequent complications in Charcot-Marie-Tooth disease (CMT) patients, often requiring orthopedic surgery. However, there are no prospective, randomized studies on surgical management, and there is variation in the approaches among centers both within and between countries. METHODS: In this study we assessed the frequency of foot deformities and surgery among patients recruited into the Inherited Neuropathies Consortium (INC). We also designed a survey addressed to orthopedic surgeons at INC centers to determine whether surgical approaches to orthopedic complications in CMT are variable. RESULTS: Foot deformities were reported in 71% of CMT patients; 30% of the patients had surgery. Survey questions were answered by 16 surgeons working in different specialized centers. Most of the respondents were foot and ankle surgeons. There was marked variation in surgical management. DISCUSSION: Our findings confirm that the approaches to orthopedic management of CMT are varied. We identify areas that require further research. Muscle Nerve 57: 255-259, 2018.

Cost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseases.

Childhood-onset muscle disorders are genetically heterogeneous. Diagnostic workup has traditionally included muscle biopsy, protein-based studies of muscle specimens, and candidate gene sequencing. High throughput or massively parallel sequencing is transforming the approach to diagnosis of rare diseases; however, evidence for cost-effectiveness is lacking. Patients presenting with suspected congenital muscular dystrophy or nemaline myopathy were ascertained over a 15-year period. Patients were investigated using traditional diagnostic approaches. Undiagnosed patients were investigated using either massively parallel sequencing of a panel of neuromuscular disease genes panel, or whole exome sequencing. Cost data were collected for all diagnostic investigations. The diagnostic yield and cost effectiveness of a molecular approach to diagnosis, prior to muscle biopsy, were compared with the traditional approach. Fifty-six patients were analysed. Compared with the traditional invasive muscle biopsy approach, both the neuromuscular disease panel and whole exome sequencing had significantly increased diagnostic yields (from 46 to 75% for the neuromuscular disease panel, and 79% for whole exome sequencing), and reduced the cost per diagnosis from USD$16,495 (95% CI: $12,413-$22,994) to USD$3706 (95% CI: $3086-$4453) for the neuromuscular disease panel and USD $5646 (95% CI: $4501-$7078) for whole exome sequencing. The neuromuscular disease panel was the most cost-effective, saving USD$17,075 (95% CI: $10,654-$30,064) per additional diagnosis, over the traditional diagnostic pathway. Whole exome sequencing saved USD$10,024 (95% CI: $5795-$17,135) per additional diagnosis. This study demonstrates the cost-effectiveness of investigation using massively parallel sequencing technologies in paediatric muscle disease. The findings emphasise the value of implementing these technologies in clinical practice, with particular application for diagnosis of Mendelian diseases, and provide evidence crucial for government subsidy and equitable access.

Erythrocyte-derived nano-probes functionalized with antibodies for targeted near infrared fluorescence imaging of cancer cells.

Constructs derived from mammalian cells are emerging as a new generation of nano-scale platforms for clinical imaging applications. Herein, we report successful engineering of hybrid nano-structures composed of erythrocyte-derived membranes doped with FDA-approved near infrared (NIR) chromophore, indocyanine green (ICG), and surface-functionalized with antibodies to achieve molecular targeting. We demonstrate that these constructs can be used for targeted imaging of cancer cells in vitro. These erythrocyte-derived optical nano-probes may provide a potential platform for clinical translation, and enable molecular imaging of cancer biomarkers.

Characteristics of non-diabetic foot ulcers in Western Sydney, Australia.

BACKGROUND: There are few studies investigating the characteristics, risk factors and socioeconomic status of patients with non-diabetic foot ulcers. The aim of this study was to explore the characteristics of non-diabetic foot ulcers in a large tertiary referral outpatient hospital setting in Western Sydney, Australia. METHODS: From 2011 to 2013, data from 202 patients with non-diabetic foot ulcers during their initial visit were retrospectively extracted for analysis from Westmead Hospital's Foot Wound Clinic Registry. Data including demographics, socioeconomic status and foot ulcer characteristics were recorded on a standardised data collection form. RESULTS: Demographics and physical characteristics were: 54 % male, median age 78 years [interquartile range (IQR): 64-87], median body mass index (BMI) of 23.8 kg/m(2) (IQR: 20-26.9), 35 % had loss of protective sensation and the median postcode score for socioeconomic status was 996 (IQR: 935-1034). Foot ulcer characteristics were: median cross-sectional area of 1.2 cm(2) (IQR: 0.3-5.0), 30.5 % plantar and 27 % dorsal, 22.1 % University of Texas (UT) Wound Classification for Diabetic Foot Ulcers Grade of 1C-3C (with ischaemia). CONCLUSIONS: Unlike diabetic foot ulcers, non-diabetic foot ulcers largely affected older males and females. In accordance with diabetic foot ulcer characteristics, socioeconomic status was not related to non-diabetic foot ulcers in Western Sydney. Based on the findings of this study the epidemiological pattern of non-diabetic foot ulceration and its pathogenesis requires further investigation.

Muscle weakness in children with neurofibromatosis type 1.

AIM: To investigate if children with neurofibromatosis type 1 (NF1) have reduced muscle strength compared with children with typical development. METHOD: Maximal isometric strength of 15 upper and lower limb muscle groups was evaluated in 30 children with NF1 (16 males, 14 females; aged 4-16y) and 30 age-, sex-, height-, and weight-matched controls using hand-held dynamometry by a single evaluator. Both the left and right sides were assessed. RESULTS: Children with NF1 were significantly weaker than children with typical development across all 15 muscle groups assessed (p<0.05). Apart from elbow flexion, there were no differences between the left and right sides (p>0.05). Magnitude of differences between the children with NF1 compared with the controls ranged from 3% to 43%. Males and females were equally affected. INTERPRETATION: This study shows that children with NF1 have reduced muscle strength compared with children with typical development. This muscle weakness is present from the earliest stages of the disease assessed and persists throughout childhood with no sex difference. These results support recent evidence from mouse studies that NF1 is associated with a primary myopathy.

Interventions for congenital talipes equinovarus (clubfoot).

BACKGROUND: Congenital talipes equinovarus (CTEV), which is also known as clubfoot, is a common congenital orthopaedic condition characterised by an excessively turned in foot (equinovarus) and high medial longitudinal arch (cavus). If left untreated it can result in long-term disability, deformity and pain. Interventions can be conservative (such as splinting or stretching) or surgical. The review was first published in 2012 and we reviewed new searches in 2013 (update published 2014). OBJECTIVES: To evaluate the effectiveness of interventions for CTEV. SEARCH METHODS: On 29 April 2013, we searched CENTRAL (2013, Issue 3 in The Cochrane Library), MEDLINE (January 1966 to April 2013), EMBASE (January 1980 to April 2013), CINAHL Plus (January 1937 to April 2013), AMED (1985 to April 2013), and the Physiotherapy Evidence Database (PEDro to April 2013). We also searched for ongoing trials in the WHO International Clinical Trials Registry Platform (2006 to July 2013) and ClinicalTrials.gov (to November 2013). We checked the references of included studies. We searched NHSEED, DARE and HTA for information for inclusion in the Discussion. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating interventions for CTEV. Participants were people of all ages with CTEV of either one or both feet. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in included trials and extracted the data. We contacted authors of included trials for missing information. We collected adverse event information from trials when it was available. MAIN RESULTS: We identified 14 trials in which there were 607 participants; one of the trials was newly included at this 2014 update. The use of different outcome measures prevented pooling of data for meta-analysis even when interventions and participants were comparable. All trials displayed bias in four or more areas. One trial reported on the primary outcome of function, though raw data were not available to be analysed. We were able to analyse data on foot alignment (Pirani score), a secondary outcome, from three trials. Two of the trials involved participants at initial presentation. One reported that the Ponseti technique significantly improved foot alignment compared to the Kite technique. After 10 weeks of serial casting, the average total Pirani score of the Ponseti group was 1.15 (95% confidence interval (CI) 0.98 to 1.32) lower than that of the Kite group. The second trial found the Ponseti technique to be superior to a traditional technique, with average total Pirani scores of the Ponseti participants 1.50 lower (95% CI 0.72 to 2.28) after serial casting and Achilles tenotomy. A trial in which the type of presentation was not reported found no difference between an accelerated Ponseti or standard Ponseti treatment. At the end of serial casting, the average total Pirani scores in the standard group were 0.31 lower (95% CI -0.40 to 1.02) than the accelerated group. Two trials in initial cases found relapse following Ponseti treatment was more likely to be corrected with further serial casting compared to the Kite groups which more often required major surgery (risk difference 25% and 50%). There is a lack of evidence for different plaster casting products, the addition of botulinum toxin A during the Ponseti technique, different types of major foot surgery, continuous passive motion treatment following major foot surgery, or treatment of relapsed or neglected cases of CTEV. Most trials did not report on adverse events. In trials evaluating serial casting techniques, adverse events included cast slippage (needing replacement), plaster sores (pressure areas) and skin irritation. Adverse events following surgical procedures included infection and the need for skin grafting. AUTHORS' CONCLUSIONS: From the limited evidence available, the Ponseti technique produced significantly better short-term foot alignment compared to the Kite technique and compared to a traditional technique. The quality of this evidence was low to very low. An accelerated Ponseti technique may be as effective as a standard technique, according to moderate quality evidence. Relapse following the Kite technique more often led to major surgery compared to relapse following the Ponseti technique. We could draw no conclusions from other included trials because of the limited use of validated outcome measures and lack of available raw data. Future randomised controlled trials should address these issues.

How does rectus femoris fibrosis affect gait?

We report on a female patient with stiff-knee gait resulting from rectus femoris fibrosis, following multiple injections into the quadriceps musculature. Treatment planning and outcome were aided by instrumented three-dimensional gait analysis. One year after surgery, improvements were found in walking speed, step length, anterior pelvic tilt, knee flexion in swing, and ankle dorsiflexion in swing. Instrumented three-dimensional gait analysis was a useful tool for characterizing gait impairments and detecting changes after surgical intervention. Intramuscular injections into the rectus femoris muscle should be avoided to prevent stiff-knee gait and associated disability.

Relationship between cognitive dysfunction, gait, and motor impairment in children and adolescents with neurofibromatosis type 1.

AIM: Motor skill impairment and cognitive dysfunction are commonly reported features of neurofibromatosis type 1 (NF1). We characterized and determined the relationship between motor impairment, gait variables, and cognitive function in children and adolescents with NF1. METHOD: Motor function, gait, and neurocognitive abilities were assessed in 46 children and adolescents with NF1 (26 males, 20 females; age range 7-17 y; mean age 11 y 1 mo, SD 3 y 2 mo). Tests to establish correlations between neurocognitive, motor, and gait variables were performed. RESULTS: Compared with normative data, 28/39 of our NF1 cohort demonstrated impaired performance for balance and upper limb coordination and 16/38 for running speed and agility. Gait data revealed a strategy to preserve balance at the expense of velocity, with the unexpected exception of a tendency for reduced base of support. Neurocognitive testing confirmed mean IQ in the low average range (86.0) and deficits in spatial working memory and strategy generation. Significant correlations between a number of neurocognitive measures and motor abilities and gait were identified. The largest associations were between gait width and spatial working memory (r=0.594) and running speed and agility with strategy generation (r=0.549). INTERPRETATION: We have identified a relationship between balance, running speed and agility, gait, and cognition in children with NF1. Findings suggest a shared abnormal neurodevelopmental process underlying some cognitive and motor abilities in NF1. Results are discussed within the context of evidence highlighting abnormal dopamine-mediated corticostriatal circuitry in NF1.