A biomechanical investigation of seated balance and upright mobility with a robotic exoskeleton in individuals with a spinal cord injury

Spinal cord injury (SCI) is a complex medical condition with multiple sequelae. The level and severity of a lesion will determine the degree of disability and associated co- morbidities, the most obvious of which is paralysis. Other concomitant issues, such as muscle contractures, poor seated posture and fear of falling, can also lead to a reduced quality of life. Although there is currently no cure for SCI, many of the comorbidities can be managed or mitigated through technology and physical rehabilitation practices.The aim of this thesis was to inform spinal cord injury (SCI) mobility rehabilitation, focusing on postural control and upright stepping using robotic assisted gait training (RAGT). A systematic review investigating RAGT use in SCI concluded that although RAGT has the potential to benefit upright locomotion of SCI individuals, it should not replace other therapies but should be incorporated into a multi-modality rehabilitation approach.Seated postural control, upper-body posture and fear-of-falling in SCI individuals were also explored. Stability performance and control demand were compared between high- and low-level injury groups as was fear-of-falling. An individualised limit of stability boundary (LOS) facilitated the differentiation between high- and low-level injuries during static tasks; however, its use during dynamic tasks was limited and potentially influenced by fear-of-falling.Few studies have quantified the user’s motion inside a lower limb robotic exoskeleton (LEXO), and none have reported marker placement repeatability. Standard error of measurement was reported for three-dimensional trunk and pelvic orientations and hip, knee and ankle angles in the sagittal plane during level walking. This revealed the marker set and placement to produce good levels of agreement between visits, with most values falling between the accepted standard of 2-5o. These findings indicated that the marker placement was repeatable and could be used in the subsequent chapters involving motion capture of overground walking.Three-dimensional gait parameters of able-bodied individuals walking with and without a LEXO at two speeds (comfortable (CMBL) and speed-matched (SLOW) to the LEXO) were investigated. Statistical parametric mapping revealed significantly different waveforms at the ANOVA level for all kinematic variables, however minimal differences in sagittal plane lower limb kinematics were identified between LEXO and SLOW gait, suggesting LEXO gait resembled slow walking when speed-matched. Altered kinematics of the pelvis and trunk during LEXO use suggest that overground exoskeletons may provide a training environment benefiting postural control training.Finally, the biomechanical characteristics of able-bodied and SCI users walking in an overground LEXO were investigated. Variables associated with neuroplasticity in SCI (hip extension and lower limb un-loading) were not significantly different between groups, indicating that afferent stimuli to facilitate neuroplastic adaptations in individuals with a SCI can be generated during LEXO gait. Upper-body orientation facilitated stepping and maintained balance, thereby requiring the participant’s active involvement.This thesis has provided evidence that LEXOs can deliver appropriate stimuli for upright stepping and that upper-body engagement can facilitate postural control training, potentially leading to improved seated postural control

The effects of robot assisted gait training on temporal-spatial characteristics of people with spinal cord injuries: a systematic review

Context: Robotic assisted gait training (RAGT) technology can be used as a rehabilitation tool or as an assistive device for spinal cord injured (SCI) individuals. Its impact on upright stepping characteristics of SCI individuals using treadmill or overground robotic exoskeleton systems has yet to be established.Objective: To systematically review the literature and identify if overground or treadmill based RAGT use in SCI individuals elicited differences in temporal-spatial characteristics and functional outcome measures.Methods:A systematic search of the literature investigating overground and treadmill RAGT in SCIs was undertaken excluding case-studies and case-series. Studies were included if the primary outcomes were temporal-spatial gait parameters. Study inclusion and methodological quality were assessed and determined independently by two reviewers. Methodological quality was assessed using a validated scoring system for randomized and non-randomized trials.Results: Twelve studies met all inclusion criteria. Participant numbers ranged from 5-130 with injury levels from C2 to T12, American Spinal Injuries Association A-D. Three studies used overground RAGT systems and the remaining nine focused on treadmill based RAGT systems. Primary outcome measures were walking speed and walking distance. The use of treadmill or overground based RAGT did not result in an increase in walking speed beyond that of conventional gait training and no studies reviewed enabled a large enough improvement to facilitate community ambulation.Conclusion: The use of RAGT in SCI individuals has the potential to benefit upright locomotion of SCI individuals. Its use should not replace other therapies but be incorporated into a multi-modality rehabilitation approach

Differential responses of captive southern hairy-nosed wombats (Lasiorhinus latifrons) to the presence of faeces from different species and male and female conspecifics

The southern hairy-nosed wombat (Lasiorhinus latifrons) appears to use scent marking, including defaecation, for social communication in the wild. This premise assumes that the receiver wombat is able to distinguish between faeces from different sources. To examine this theory, four types of faeces (male wombat, female wombat, dingo and a plastic control) were placed into the enclosures of 12 captive wombats. Behaviour, inter-individual distance and enclosure use were recorded during the period of placement, as well as the period before and the period after. When faeces were present, the wombats used concealed locations more often than other periods (mean %: pre-treatment: 71.3, treatment: 75.6, post-treatment: 72.7; P < 0.05). During the same period they also reduced grazing (mean min/period: pre- treatment: 15.8, treatment: 6.9, post- treatment: 13.1; P = 0.0002) and walking 2 activity (mean min/period: pre- treatment: 85.2, treatment: 66.9, post- treatment: 78.2; P = 0.01), indicating an increased perception of risk. Wombats approached the dingo faeces 5.6 times per treatment period, which was greater than for the control (3.0; P = 0.004) or female wombat faeces (3.7; P = 0.049). They also avoided other wombats most when male wombat faeces were present (8.3 retreats/period) compared to the control (4.5; P = 0.02), or female wombat (4.3; P = 0.01). There was a residual effect of increased wombat avoidance the period after presentation of dingo faeces (9.6; P ≤ 0.05). It is concluded that the southern hairy-nosed wombat can differentiate between faeces from different species and sex of conspecifics, and that predator faeces and those from male conspecifics increase wombat avoidance behaviour either during or after presentation

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe