Research ethics and artificial intelligence for global health: perspectives from the global forum on bioethics in research.

BACKGROUND: The ethical governance of Artificial Intelligence (AI) in health care and public health continues to be an urgent issue for attention in policy, research, and practice. In this paper we report on central themes related to challenges and strategies for promoting ethics in research involving AI in global health, arising from the Global Forum on Bioethics in Research (GFBR), held in Cape Town, South Africa in November 2022. METHODS: The GFBR is an annual meeting organized by the World Health Organization and supported by the Wellcome Trust, the US National Institutes of Health, the UK Medical Research Council (MRC) and the South African MRC. The forum aims to bring together ethicists, researchers, policymakers, research ethics committee members and other actors to engage with challenges and opportunities specifically related to research ethics. In 2022 the focus of the GFBR was "Ethics of AI in Global Health Research". The forum consisted of 6 case study presentations, 16 governance presentations, and a series of small group and large group discussions. A total of 87 participants attended the forum from 31 countries around the world, representing disciplines of bioethics, AI, health policy, health professional practice, research funding, and bioinformatics. In this paper, we highlight central insights arising from GFBR 2022. RESULTS: We describe the significance of four thematic insights arising from the forum: (1) Appropriateness of building AI, (2) Transferability of AI systems, (3) Accountability for AI decision-making and outcomes, and (4) Individual consent. We then describe eight recommendations for governance leaders to enhance the ethical governance of AI in global health research, addressing issues such as AI impact assessments, environmental values, and fair partnerships. CONCLUSIONS: The 2022 Global Forum on Bioethics in Research illustrated several innovations in ethical governance of AI for global health research, as well as several areas in need of urgent attention internationally. This summary is intended to inform international and domestic efforts to strengthen research ethics and support the evolution of governance leadership to meet the demands of AI in global health research.

The long-term effects of wearing moderate minimalist shoes on a child's foot strength, muscle structure and balance: A randomised controlled trial.

BACKGROUND: From retrospective research, it is believed that children who predominantly spend their time shod have poorer foot strength and performance than those who are predominantly barefoot. Children's foot motion has been shown to be adversely affected by standard school shoes; however, the long-term effect of moderate minimalist shoes on foot strength, muscle structure and balance in children is unknown. RESEARCH QUESTION: Does wearing moderate minimalist shoes, compared to stiff shoes, benefit a child's foot strength, muscle structure and performance over time? METHODS: Seventy healthy children (9-12 yr) were randomly assigned to wear standard (control), or minimalist shoes (experimental) at school, for nine months. Cross-sectional areas (CSA) of Abductor Hallucis (AH) and Flexor Digitorum Brevis (FDB) muscles, and toe flexor strength (TFS) of hallux and lesser toes separately, were primary outcome measures. Single leg balance (SLB), Y-balance test (YBT) and standing long jump (SLJ) were secondary outcome measures. Pre- and post-intervention measurements were analysed for between group differences with ANCOVA. RESULTS: Minimalist shoes resulted in moderate but statistically non-significant increases in muscle CSA (AH η2p =.04, FDB η2p =.05) and TFS (hallux η2p =.05, lesser toes η2p =.04). Significant moderate to large improvements in YBT in the experimental group were found in the postero-medial (P = .04, η2p =.07) and postero-lateral (P = .01, η2p =.10) directions. YBT (anterior, postero-medial and postero-lateral) was correlated with hallux TFS (R =.29,.27 and.33 respectively), lesser toes TFS (R =.28,.35 and.38 respectively) and SLJ (R =.30,.39 and.57 respectively). CSA of FDB was correlated with SLJ (R =.34) and SLB (R =.42). SIGNIFICANCE: Wearing moderate minimalist shoes long-term improves balance in children. TFS is correlated with better balance and SLJ. Moderate minimalist school shoes are recommended for children.

Excellent reliability of toe strength measurements in children aged ten to twelve years achieved with a novel fixed dynamometer.

BACKGROUND: Stronger toe flexor muscles improve performance outcomes in children, including balance, sprinting, jumping and side stepping. Toe flexor strength (TFS) is recommended as part of the clinical assessment of foot function in children. Fixed dynamometry, rather than handheld, is the gold standard of measurement; however, it can be prohibitively costly. No fixed dynamometer reliability studies on toe flexion have been conducted in children to date. RESEARCH QUESTIONS: Does the novel fixed hand-held dynamometer (HHD) protocol provide reliable intra-rater and test-retest measurements of toe flexor strength in children aged 10 to 12? METHODS: Two trials were recorded from 14 healthy children (10-12 years), 7-14 days apart by the same rater. A Lafayette HHD (model 01163) measured peak force. The HHD was secured in a mobile custom mould below a step with a strap, which secured the foot of the participant. The receptor pads of the HHD were level with the upper surface of the step, maintaining neutral toe joints at rest. The participant was seated on an adjustable stool to ensure the hip, knee and ankle were each at 90° flexion, with the testing foot flat on the upper surface of the step. The averages of three maximal five second efforts were used for data analysis using a two-way mixed effects model with repeated measures ANOVA (intraclass correlation coefficient ICC 3,3). Standard error of measurement (SEM) was calculated to determine the absolute between trial variability. RESULTS: The novel fixed HHD protocol provided excellent test-retest reliability with small measurement error for hallux (ICC 3,3 = 0.93, 95 % CI 0.78-0.98, SEM = 4.31 N) and lesser toe flexor strength testing (ICC 3,3 = 0.96, 95 % CI 0.87-0.99, SEM = 1.86 N). SIGNIFICANCE: The fixed HHD protocol described in this study has excellent reliability for the test-retest evaluation of children's toe flexor strength.

The evidence for improving balance by strengthening the toe flexor muscles: A systematic review.

BACKGROUND: Poor postural balance in the upright position is strongly correlated to morbidities, such as falls in older adult populations and to lower limb injuries in the younger populations. Good postural balance depends on muscular strength and the integration of neurological and muscular feedback mechanisms throughout the body. Since the interface with the ground is the plantar surface of each foot, an improved understanding of the role of foot muscles in postural balance is warranted. RESEARCH QUESTION: Does improved toe flexor strength result in better postural balance, across the lifespan? METHODS: A systematic review was conducted of papers from 1900 to 2019 inclusive, from five databases. Inclusion and exclusion criteria were established prior to selection. Inclusion criteria were: observational and longitudinal studies, healthy subjects, at least one balance and one toe flexor strength test conducted. Exclusion criteria were: subjects with a pathology/disability, case study, systematic or literature review. Two examiners assessed a study's suitability for inclusion in this review, based on the above criteria. Study quality was assessed using the Critical Appraisal Skills Program Tools. The type of studies and methodological heterogeneity precluded the feasibility of conducting a meta-analysis. RESULTS: Nine studies were included. In each study, participants were over sixty years of age, and over 73 % of them were female. No study was found for a younger population group. There were seven cross-sectional studies, two randomized control trials and there was one case-control study. All studies provided evidence of directly proportional, clinically significant correlations between toe flexor strength and postural balance. SIGNIFICANCE: Toe flexor strength contributes to improved postural balance for people over the age of 60. Research is needed to establish the relationship between foot muscle strength and balance in younger adults and children.

The global forum on bioethics in research meeting, "ethics of alternative clinical trial designs and methods in low- and middle-income country research": emerging themes and outputs.

Alternative clinical trial designs and methods are increasingly being used in place of the conventional individually randomised controlled trial (RCT) in high-income and in low-income and middle-income country (LMIC) research. These approaches - including adaptive, cluster-randomised and stepped-wedge designs and controlled human infection models - offer a number of potential advantages, including being more efficient and making the clinical trial process more socially acceptable. However, these designs and methods are generally not familiar to researchers, research ethics committees and regulators and their ethical implications have not received sufficient international attention from the bioethics, research, and policymaking communities working together. The ethics of alternative clinical trial designs and methods in LMIC research was chosen as a topic for the 2017 Global Forum on Bioethics in Research (GFBR). The meeting opened a global dialogue about this emerging issue in research ethics and gave voice to the LMIC perspective. It identified the need to take a multidisciplinary approach and to develop capacity amongst researchers and research ethics committees and regulators to propose, review and regulate these novel designs and methods. Building skills and infrastructure will empower researchers to choose from a broad range of designs and methods and adopt the most scientifically suitable, efficient, ethical and context-appropriate of these. The need for capacity development is most pressing from the LMIC perspective, where limited resources create an urgency to seek the most efficient trial design and method. The aim of this paper is to encourage broad debate about this complex area of research. By opening up this debate, GFBR aims to promote the appropriate and ethical use of novel designs and methods so their full potential to address the health needs in LMICs can be realised.

The global forum on bioethics in research meeting, "ethics of research in pregnancy": emerging consensus themes and outputs.

Research during pregnancy is affected by multiple ethical challenges which have not received sufficient international attention and consideration from the bioethics, clinical, and policymaking communities working together. Unresolved ethical questions about research in pregnancy have significant detrimental impacts on maternal and newborn health, in part because they inhibit an evidence base being developed on the efficacy and safety of medicines and health interventions for pregnant women. These problems are compounded in low- and middle-income country (LMIC) settings due to variability in regulatory provisions, the burden of maternal morbidity and mortality, and many social and cultural conventions that impact on pregnant women's ability to participate in research. Research in pregnancy was chosen as a topic for the 2016 Global Forum on Bioethics in Research (GFBR) meeting, and its timeliness was all the more apparent given the 2016 Zika outbreak, which has deeply affected the Latin American region. The meeting's emerging consensus themes and outputs epitomized the core aims of the GFBR-to give voice to LMIC perspectives as a priority in dialogue about global health research ethics and to promote collaboration. In this instance, the GFBR meeting catalyzed a strong, unified drive to push researchers and policymakers to include pregnant women in research by default: given the complex nature of the topic, this is a significant achievement in addressing an important question of social justice.

In-shoe multi-segment foot kinematics of children during the propulsive phase of walking and running.

Certain styles of children's shoes reduce 1st metatarsophalangeal joint (MTPJ) and midfoot motion during propulsion of walking. However, no studies have investigated if the splinting effect of shoes on children's 1st MTPJ and midfoot motion occurs during running. This study investigated the effect of sports shoes on multi-segment foot kinematics of children during propulsion of walking and running. Twenty children walked and ran at a self-selected velocity while barefoot and shod in a random order. Reflective markers were used to quantify sagittal plane motion of the 1st MTPJ and three-dimensional motion of the midfoot and ankle. Gait velocity increased during shod walking and running and was considered a covariate in the statistical analysis. Shoes reduced 1st MTPJ motion during propulsion of walking from 36.0° to 10.7° and during running from 31.5° to 12.6°. Midfoot sagittal plane motion during propulsion reduced from 22.5° to 6.2° during walking and from 27.4° to 9.6° during running. Sagittal plane ankle motion during propulsion increased during shod running from 26.7° to 34.1°. During propulsion of walking and running, children's sports shoes have a splinting effect on 1st MTPJ and midfoot motion which is partially compensated by an increase in ankle plantarflexion during running.

The zebrafish reference genome sequence and its relationship to the human genome.

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

Effect of thong style flip-flops on children's barefoot walking and jogging kinematics.

BACKGROUND: Thong style flip-flops are a popular form of footwear for children. Health professionals relate the wearing of thongs to foot pathology and deformity despite the lack of quantitative evidence to support or refute the benefits or disadvantages of children wearing thongs. The purpose of this study was to compare the effect of thong footwear on children's barefoot three dimensional foot kinematics during walking and jogging. METHODS: Thirteen healthy children (age 10.3 ± 1.6 SD years) were recruited from the metropolitan area of Sydney Australia following a national press release. Kinematic data were recorded at 200 Hz using a 14 camera motion analysis system (Cortex, Motion Analysis Corporation, Santa Rosa, USA) and simultaneous ground reaction force were measured using a force platform (Model 9281B, Kistler, Winterthur, Switzerland). A three-segment foot model was used to describe three dimensional ankle, midfoot and one dimensional hallux kinematics during the stance sub-phases of contact, midstance and propulsion. RESULTS: Thongs resulted in increased ankle dorsiflexion during contact (by 10.9°, p; = 0.005 walk and by 8.1°, p; = 0.005 jog); increased midfoot plantarflexion during midstance (by 5.0°, p; = 0.037 jog) and propulsion (by 6.7°, p; = 0.044 walk and by 5.4°, p;= 0.020 jog); increased midfoot inversion during contact (by 3.8°, p;= 0.042 jog) and reduced hallux dorsiflexion during walking 10% prior to heel strike (by 6.5°, p; = 0.005) at heel strike (by 4.9°, p; = 0.031) and 10% post toe-off (by 10.7°, p; = 0.001). CONCLUSIONS: Ankle dorsiflexion during the contact phase of walking and jogging, combined with reduced hallux dorsiflexion during walking, suggests a mechanism to retain the thong during weight acceptance. Greater midfoot plantarflexion throughout midstance while walking and throughout midstance and propulsion while jogging may indicate a gripping action to sustain the thong during stance. While these compensations exist, the overall findings suggest that foot motion whilst wearing thongs may be more replicable of barefoot motion than originally thought.

Manual testing for ankle instability.

AIM: To assess inter-rater reliability of ankle manual tests. We also correlated the manual tests with the Cumberland Ankle Instability Tool (CAIT). METHOD: One ankle from each of 60 participants was assessed using four different manual tests (anterior drawer in supine and crook lying, talar tilt, inversion tilt). Three different raters, varying in experience, tested each participant. The CAIT questionnaire was also administered. The study received ethics approval from the University of Sydney Human Research Ethics Committee. Intraclass correlation coefficients (ICC), standard error of the mean (SEM) and percent close agreement (PCA) were used to determine reliability of the four tests. Pearson's correlation coefficients were used to determine relationships between the manual tests and CAIT scores. RESULTS: Inter-rater reliability for the four manual tests was poor regardless of therapist's experience (ICC([1,1]) -0.12 to 0.33; SEM 0.93-1.69). Correlations between the CAIT and manual tests were also low varying between r = -0.12 and -0.42. CONCLUSIONS: Inter-rater reliability was poor for manual tests of ankle stability. Reliability may be improved by using a grading scale with fewer intervals. The CAIT scores and manual tests correlated poorly, potentially reflecting the variety of conditions leading to ankle instability.

Effect of children's shoes on gait: a systematic review and meta-analysis.

BACKGROUND: The effect of footwear on the gait of children is poorly understood. This systematic review synthesises the evidence of the biomechanical effects of shoes on children during walking and running. METHODS: Study inclusion criteria were: barefoot and shod conditions; healthy children aged ≤ 16 years; sample size of n > 1. Novelty footwear was excluded. Studies were located by online database-searching, hand-searching and contact with experts. Two authors selected studies and assessed study methodology using the Quality Index. Meta-analysis of continuous variables for homogeneous studies was undertaken using the inverse variance approach. Significance level was set at P < 0.05. Heterogeneity was measured by I2. Where I2 > 25%, a random-effects model analysis was used and where I2 < 25%, a fixed-effects model was used. RESULTS: Eleven studies were included. Sample size ranged from 4-898. Median Quality Index was 20/32 (range 11-27). Five studies randomised shoe order, six studies standardised footwear. Shod walking increased: velocity, step length, step time, base of support, double-support time, stance time, time to toe-off, sagittal tibia-rearfoot range of motion (ROM), sagittal tibia-foot ROM, ankle max-plantarflexion, Ankle ROM, foot lift to max-plantarflexion, 'subtalar' rotation ROM, knee sagittal ROM and tibialis anterior activity. Shod walking decreased: cadence, single-support time, ankle max-dorsiflexion, ankle at foot-lift, hallux ROM, arch length change, foot torsion, forefoot supination, forefoot width and midfoot ROM in all planes. Shod running decreased: long axis maximum tibial-acceleration, shock-wave transmission as a ratio of maximum tibial-acceleration, ankle plantarflexion at foot strike, knee angular velocity and tibial swing velocity. No variables increased during shod running. CONCLUSIONS: Shoes affect the gait of children. With shoes, children walk faster by taking longer steps with greater ankle and knee motion and increased tibialis anterior activity. Shoes reduce foot motion and increase the support phases of the gait cycle. During running, shoes reduce swing phase leg speed, attenuate some shock and encourage a rearfoot strike pattern. The long-term effect of these changes on growth and development are currently unknown. The impact of footwear on gait should be considered when assessing the paediatric patient and evaluating the effect of shoe or in-shoe interventions.

The reliability and validity of a three-camera foot image system for obtaining foot anthropometrics.

The purpose was to develop a foot image capture and measurement system with web cameras (the 3-FIS) to provide reliable and valid foot anthropometric measures with efficiency comparable to that of the conventional method of using a handheld anthropometer. Eleven foot measures were obtained from 10 subjects using both methods. Reliability of each method was determined over 3 consecutive days using the intraclass correlation coefficient and root mean square error (RMSE). Reliability was excellent for both the 3-FIS and the handheld anthropometer for the same 10 variables, and good for the fifth metatarsophalangeal joint height. The RMSE values over 3 days ranged from 0.9 to 2.2 mm for the handheld anthropometer, and from 0.8 to 3.6 mm for the 3-FIS. The RMSE values between the 3-FIS and the handheld anthropometer were between 2.3 and 7.4 mm. The 3-FIS required less time to collect and obtain the final variables than the handheld anthropometer. The 3-FIS provided accurate and reproducible results for each of the foot variables and in less time than the conventional approach of a handheld anthropometer.

Effects of ankle-foot orthoses for children with hemiplegia on weight-bearing and functional ability.

PURPOSE: To compare the effects of a leaf spring ankle-foot orthosis (LAFO) and a hinged AFO with plantar flexion stop with that of shoe only on weight-bearing and function in children with hemiplegia. METHODS: The study used an experimental single-subject alternating treatment design with replication. Outcomes measured were weight-bearing symmetry, weight-bearing on the hemiplegic rear foot compared with that of the forefoot, functional ability, and child and parent preference. RESULTS: Both AFOs increased relative contact area of the hemiplegic foot. The LAFO increased relative force through the hemiplegic foot. There was increased pressure through the rear foot, time spent on the rear foot, and force through the forefoot. Rear foot contact area increased in the LAFO. Neither AFO affected function. Patient preference for AFO condition was inconsistent. CONCLUSION: Both AFOs increased weight-bearing through the hemiplegic foot and rear foot, indicative of potential benefit to growth. Neither the LAFO nor the hinged AFO with plantar flexion stop improved function of the children.

Inter-tester reliability and precision of manual muscle testing and hand-held dynamometry in lower limb muscles of children with spina bifida.

Reliability and measurement precision of manual muscle testing (MMT) and hand-held dynamometry (HHD) were compared for children with spina bifida. Strength measures were obtained of the hip flexors, hip abductors, and knee extensors of 20 children (10 males, 10 females; mean age 9 years 10 months; range: 5 to 15 years) by two experienced physical therapists and a student physical therapist. Inter-tester reliability [ICC(2,1)] for HHD varied from 0.76 to 0.83, indicating excellent reliability for the three muscle groups. Inter-tester reliability for MMT was 0.75 for the hip abductor muscle group, indicating good reliability, and 0.37 to 0.40 for the remaining muscle groups. The minimum detectable change was 15N for HHD and 1 scale unit of a 0 to 5 MMT scale. The results suggest a situation-specific solution to the question of which method to use. To detect small strength changes over time in children with spina bifida, MMT should be used when the child has insufficient strength to move the limb against gravity; otherwise, HHD should be used.

Effect of foot morphology on center-of-pressure excursion during barefoot walking.

BACKGROUND: The path of the center of pressure during walking varies among individuals by deviating to a greater or lesser extent toward the medial or lateral border of the foot. It is unclear whether this variance is systematic and is affected by foot posture. The aim of this study was to explore the relationship between foot morphology and center-of-pressure excursion during barefoot walking. METHODS: Pressure data were collected from 83 participants whose foot type had been classified as supinated, normal, or pronated according to the Foot Posture Index. Three center-of-pressure variables were analyzed: medial excursion area, lateral excursion area, and total excursion area. RESULTS: Across the spectrum of foot types, we found that the more supinated a participant's foot posture, the larger the area of lateral center-of-pressure excursion, and, conversely, the more pronated the foot posture, the smaller the area of lateral center-of-pressure excursion. Furthermore, the supinated foot type had a relatively larger center-of-pressure total excursion area, and the pronated foot type had a relatively smaller center-of-pressure total excursion area. CONCLUSIONS: These results indicate the importance of assessing foot posture when measuring center of pressure and may help explain regional differences in pain and injury location among foot types.

Effective orthotic therapy for the painful cavus foot: a randomized controlled trial.

Patients with a cavus or high-arched foot frequently experience foot pain, which can lead to significant limitation in function. Custom foot orthoses are widely prescribed to treat cavus foot pain. However, no clear guidelines for their construction exist, and there is limited evidence of their efficacy. In a randomized, single-blind, sham-controlled trial, the effect of custom foot orthoses on foot pain, function, quality of life, and plantar pressure loading in people with a cavus foot type was investigated. One hundred fifty-four participants with chronic musculoskeletal foot pain and bilateral cavus feet were randomly assigned to a treatment group receiving custom foot orthoses (n = 75) or to a control group receiving simple sham insoles (n = 79). At 3 months, 99% of the participants provided follow-up data using the Foot Health Status Questionnaire. Foot pain scores improved more with custom foot orthoses than with the control (difference, 8.3 points; 95% confidence interval [CI], 1.2 to 15.3 points; P = .022). Function scores also improved more with custom foot orthoses than with the control (difference, 9.5 points; 95% CI, 2.9 to 16.1 points; P = .005). Quality-of-life data favored custom foot orthoses, although differences reached statistical significance only for physical functioning (difference, 7.0 points; 95% CI, 1.9 to 12.1 points; P = .008). Plantar pressure improved considerably more with custom foot orthoses than with the control for all regions of the foot (difference, -3.0 N . s/cm(2); 95% CI, -3.7 to -2.4 N . s/cm(2); P < .001). In conclusion, custom foot orthoses are more effective than a control for the treatment of cavus foot pain and its associated limitation in function.

The effect of pes cavus on foot pain and plantar pressure.

BACKGROUND: Clinical management of patients with painful pes cavus is challenging because the mechanism of foot pain is poorly understood. The purpose of this study was to explore the influence of various pes cavus aetiologies on foot pain and plantar pressure characteristics, and to identify the relationship between foot pain and plantar pressure. METHODS: Seventy subjects were recruited for this study. They included 30 subjects with pes cavus of unknown aetiology (idiopathic), 10 subjects with pes cavus of neurological aetiology (neurogenic) and 30 subjects with a normal foot type. The presence and location of foot pain was recorded and barefoot plantar pressures were measured using the EMED-SF platform for the whole foot, rearfoot, midfoot and forefoot regions. FINDINGS: Subjects with pes cavus of either idiopathic or neurogenic aetiology reported a higher proportion of foot pain (60%) compared to subjects with a normal foot type (23%) (P=0.009). Pressure-time integrals under the whole foot, rearfoot and forefoot regions in pes cavus, of both idiopathic and neurogenic origin, were higher than in the normal foot type (P<0.01). Pressure-time integrals in subjects reporting foot pain were higher than for pain free subjects (P<0.001). There was a significant correlation between pressure-time integral and foot pain (r=0.49, P<0.001). INTERPRETATION: Foot pain is a common finding among individuals with pes cavus. Regardless of aetiology, pes cavus is characterized by abnormally high pressure-time integrals which are significantly related to foot pain. An understanding of the relationship between pes cavus pressure patterns and foot pain will improve the clinical management of these patients.

Characterization of the imprinted polycomb gene L3MBTL, a candidate 20q tumour suppressor gene, in patients with myeloid malignancies.

Chromosome 20q deletion is a recurrent chromosomal abnormality associated with myeloid malignancies. L3MBTL represents a strong candidate tumour suppressor gene since it lies within the common deleted region, is a member of the Polycomb-like family, encodes the human homologue of a Drosophila tumour suppressor and is expressed within haematopoietic progenitor cells. We describe the structure of L3MBTL, identify two putative promoters each associated with two CpG islands and characterize a complex pattern of alternative splicing events. Mutation analysis of the gene in patients with and without a 20q deletion identified several polymorphisms but no acquired mutations. The two CpG islands spanning promoter 2 undergo monoallelic methylation in normal haematopoietic cells consistent with imprinting of L3MBTL. Samples from patients with a 20q deletion retained either the methylated or unmethylated allele but retention of the methylated allele did not correlate with reduction in L3MBTL mRNA levels. The absence of a correlation between L3MBTL methylation and transcription could be shown to reflect loss of imprinting in one patient. In addition, our results demonstrate that inactivation of L3MBTL is not a common occurrence in patients with a 20q deletion or in cytogenetically normal patients with polycythaemia vera.

Mechanics and control of the flat versus normal foot during the stance phase of walking.

OBJECTIVE: To compare walking stance phase rearfoot and forefoot motion, ankle joint moments and extrinsic foot muscle EMG profiles between normal and pes planus feet. DESIGN: A cross-sectional comparative study. BACKGROUND: Musculoskeletal conditions are often attributed to pes planus, in which motion is assumed to be excessive and the muscle control inadequate. However, many of the speculated differences in mechanics and control between the normal and the pes planus foot have not been quantified. METHODS: Kinematic and kinetic data were obtained from video recordings of skin surface markers and a force plate, and EMG was recorded with surface electrodes. Analysis of variance was carried out to compare the group profiles. RESULTS: In the pes planus group: the forefoot was less adducted (P < .05) at toe-off, and total transverse plane range of motion, at 8 degrees versus 10 degrees, was less (P < .01); the peak plantarflexor ankle moment at push-off was greater (P < .05); the invertor moment was greater at foot flat (P < .05); for the EMG profiles, activity early in stance, relative to the mean stance phase activity was higher (P < .01) in tibialis anterior and lower (P < .05) in the peronei, soleus and medial and lateral gastrocnemius. CONCLUSIONS: Despite reaching statistical significance, the group differences were small for the task of laboratory walking at a natural pace. The main implications of the differences were for restraint of motion. The expectations of excessive motion and muscle effort in the pes planus group were therefore not substantiated. RELEVANCE: Symptomatic pes planus subjects did not reveal the expected biomechanical differences from normal subjects. The underlying causes of symptoms were not identifiable.