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Peer reviewed: True, Acknowledgements: We wish to thank our volunteers and all the recruitment partners who assisted with participant identification and referrals; Imperial College Healthcare NHS Trust, Central North West London NHS Foundation trust, Camden and Islington NHS trust, Cambridge University Hospitals NHS Foundation Trust, Norfolk and Suffolk NHS Foundation Trust, Cambridge and Peterborough NHS Foundation Trust, South Staffordshire and Shropshire NHS Foundation Trust, Manchester Mental Health NHS and Social Care Trust, Greater Manchester West NHS Foundation Trust, Pennine Care NHS Foundation Trust, Salford Royal NHS Foundation Trust, Addaction, Foundation 66 and CRI (Crime Reduction Initiative). We also wish to thank our ICCAM Consortium collaborators David Nutt, Anne Lingford-Hughes, Louise Paterson, John McGonigle, Remy Flechais, Csaba Orban, Bill Deakin, Rebecca Elliott, Anna Murphy, Eleanor Taylor, Trevor Robbins, Karen Ersche, John Suckling, Dana Smith, Laurence Reed, Filippo Passetti, Luca Faravelli, David Erritzoe, Inge Mick, Nicola Kalk, Adam Waldman, Liam Nestor, Shankar Kuchibatla, Venkataramana Boyapati, Antonio Metastasio, Yetunde Faluyi, Emilio Fernandez-Egea, Sanja Abbott, Barbara Sahakian, Valerie Voon, and Ilan Rabiner., INTRODUCTION: Negative affective states contribute to the chronic-relapsing nature of addiction. Mesolimbic dopamine D3 receptors are well placed to modulate emotion and are dysregulated in substance dependence. Selective antagonists might restore dopaminergic hypofunction, thus representing a potential treatment target. We investigated the effects of selective D3 antagonist, GSK598809, on the neural response to negative emotional processing in substance dependent individuals and healthy controls. METHODOLOGY: Functional MRI BOLD response was assessed during an evocative image task, 2 h following acute administration of GSK598809 (60 mg) or placebo in a multi-site, double-blind, pseudo-randomised, cross-over design. Abstinent drug dependent individuals (DD, n = 36) comprising alcohol-only (AO, n = 19) and cocaine-alcohol polydrug (PD, n = 17) groups, and matched controls (n = 32) were presented with aversive and neutral images in a block design (contrast of interest: aversive > neutral). Whole-brain mixed-effects and a priori ROI analyses tested for group and drug effects, with identical models exploring subgroup effects. RESULTS: No group differences in task-related BOLD signal were identified between DD and controls. However, subgroup analysis revealed greater amygdala/insular BOLD signal in PD compared with AO groups. Following drug administration, GSK598809 increased BOLD response across HC and DD groups in thalamus, caudate, putamen, and pallidum, and reduced BOLD response in insular and opercular cortices relative to placebo. Multivariate analyses in a priori ROIs revealed differential effects of D3 antagonism according to subgroup in substantia nigra; GSK598809 increased BOLD response in AO and decreased response in PD groups. CONCLUSION: Acute GSK598809 modulates the BOLD response to aversive image processing, providing evidence that D3 antagonism may impact emotional regulation. Enhanced BOLD response within D3-rich mesolimbic regions is consistent with its pharmacology and with attenuation of substance-related hypodopaminergic function. However, the lack of group differences in task-related BOLD response and the non-specific effect of GSK598809 between groups makes it difficult to ascertain whether D3 antagonism is likely to be normalising or restorative in our abstinent populations. The suggestion of differential D3 modulation between AO and PD subgroups is intriguing, raising the possibility of divergent treatment responses. Further study is needed to determine whether D3 antagonism should be recommended as a treatment target in substance dependence.

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Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Background Currently, the acceptability and efficacy of pulmonary rehabilitation for adults with severe asthma is unknown. Objective To investigate the feasibility of performing a randomized controlled trial of asthma-tailored pulmonary rehabilitation (AT-PR) versus usual care (UC). Methods Adults with severe asthma were recruited and randomized 2:1 to AT-PR and UC. The primary outcomes were recruitment, retention, and serious adverse event rates. Secondary outcome measures included those for a future trial assessing the feasibility of collecting data. Assessments were performed at baseline, 12 weeks, and 9 months including measures of physical performance, health-related quality of life, and asthma control. A recruitment rate of 30% was estimated with 95% CI of ±7%, a retention rate of 75% ± 14% if we recruited 40 patients to AT-PR, and a serious adverse event rate of 2.5%. Results Sixty-one (26%) of 238 eligible patients were recruited (38 women; mean age, 54 ± 13 years; body mass index, 32 ± 7 kg/m2; FEV1, 1.9 ± 0.7 L; FEV1/forced vital capacity, 69% ± 11%). Fifty-one patients were randomized to AT-PR (n = 34) and UC (n = 17). The retention rate was 62% for the AT-PR group and 53% for the UC group, with a serious adverse event rate of 3.3% related to the study visits. Overall collection of the outcome measures was feasible. The results of the AT-PR group were suggestive of improvements in exercise performance, health-related quality of life, and asthma control, but the UC group results were either unchanged or worsened. Conclusions Both recruitment and retention rates were within the a priori estimated 95% CI. Our results indicate that AT-PR may be efficacious for adults with severe asthma but any future intervention and trial design would need further modifications to improve acceptability and retention rate.

Classification of gait in adults with hereditary spastic paresis is limited. Our aim was to use a previously established system to classify gait.Forty-nine participants were retrospectively recruited and grouped into existing classifications based on sagittal plane knee joint kinematic data extracted from a 3D analysis. Waveform analysis was used to compare the grouped data to determine if and where differences in the subjective classifications appeared.Classification of gait patterns in adults with hereditary spastic paresis is successful. Differences between groups in line with the classification system were confirmed by statistical analysis. Crouch gait is illustrated by a flexed knee throughout stance phase. Recurvatum gait is dominated by knee hyperextension in mid-late stance. Stiff-knee gait demonstrates limited knee range of motion in stance and jump-knee gait is characterised by less knee flexion in early and mid-stance phase than all groups. Sagittal plane hip and ankle kinematics compliment group differences at the knee joint. The jump-knee group is more flexed at the hip than all groups during loading response phase and mid-stance; and the recurvatum group is more extended at the hip than the crouch, jump-knee, and stiff-knee groups during mid and late-stance phase. There is less ankle dorsiflexion throughout stance phase in the recurvatum group than in all other groups.Sagittal plane knee joint kinematic data can be subjectively used to classify gait features in adults with hereditary spastic paresis. Novel analysis show hip and ankle sagittal plane kinematics can be used to further assist classification.

Alcohol use disorder is characterised by disrupted reward learning, underpinned by dysfunctional cortico-striatal reward pathways, although relatively little is known about the biology of reward processing in populations who engage in risky alcohol use. Cues that trigger reward anticipation can be categorized according to their learnt valence (i.e., positive vs. negative outcomes) and motivational salience (i.e., incentive vs. neutral cues). Separating EEG signals associated with these dimensions is challenging because of their inherent collinearity, but the recent application of machine learning methods to single EEG trials affords a solution. Here, the Alcohol Use Disorders Identification Test (AUDIT) was used to quantify risky alcohol use, with participants split into high alcohol (HA) (n = 22, mean AUDIT score: 13.82) and low alcohol (LA) (n = 22, mean AUDIT score: 5.77) groups. We applied machine learning multivariate single-trial classification to the electroencephalography (EEG) data collected during reward anticipation. The LA group demonstrated significant valence discrimination in the early stages of reward anticipation within the cue-P3 time window (400-550 ms), whereas the HA group was insensitive to valence within this time window. Notably, the LA, but not the HA group demonstrated a relationship between single-trial variability in the early valence component and reaction times for gain and loss trials. This study evidences disrupted hypoactive valence sensitivity in the HA group, revealing potential neurophysiological markers for risky drinking behaviours which place individuals at-risk of adverse health events.

Background70%–84% of individuals with antipsychotic treatment resistance show non-response from the first episode. Emerging cross-sectional evidence comparing cognitive profiles in treatment resistant schizophrenia to treatment-responsive schizophrenia has indicated that verbal memory and language functions may be more impaired in treatment resistance. We sought to confirm this finding by comparing cognitive performance between antipsychotic non-responders (NR) and responders (R) using a brief cognitive battery for schizophrenia, with a primary focus on verbal tasks compared against other measures of cognition.DesignCross-sectional.SettingThis cross-sectional study recruited antipsychotic treatment R and antipsychotic NR across four UK sites. Cognitive performance was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS).ParticipantsOne hundred and six participants aged 18–65 years with a diagnosis of schizophrenia or schizophreniform disorder were recruited according to their treatment response, with 52 NR and 54 R cases.OutcomesComposite and subscale scores of cognitive performance on the BACS. Group (R vs NR) differences in cognitive scores were investigated using univariable and multivariable linear regressions adjusted for age, gender and illness duration.ResultsUnivariable regression models observed no significant differences between R and NR groups on any measure of the BACS, including verbal memory (ß=−1.99, 95% CI −6.63 to 2.66, p=0.398) and verbal fluency (ß=1.23, 95% CI −2.46 to 4.91, p=0.510). This pattern of findings was consistent in multivariable models.ConclusionsThe lack of group difference in cognition in our sample is likely due to a lack of clinical distinction between our groups. Future investigations should aim to use machine learning methods using longitudinal first episode samples to identify responder subtypes within schizophrenia, and how cognitive factors may interact within this.Trail registration numberREC: 15/LO/0038.

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = -0.615), while the PST medial-lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = -0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p < 0.001, SRM = -1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Background Three-dimensional gait analysis (3DGA) has not previously been considered by consensus panels of spinal cord experts for use in studies of patients with spinal cord damage (SCD), yet it is frequently used in other neurological populations, such as stroke and cerebral palsy. Research question How does 3DGA impairment based reporting guide individualised clinical decision-making in people with incomplete SCD? Methods Retrospective open cohort case series recruited 48 adults with incomplete SCD (traumatic or non-traumatic spinal cord dysfunction) referred to the Clinical Gait Analysis Service (CGAS), Melbourne, Australia. Three-dimensional gait data were used to identify gait impairments by the multidisciplinary clinical team. Gait patterns were classified using the plantarflexor-knee extension couple index and the Gait Profile Score (GPS). The reason for referral and the recommendations made post-3DGA were collated in decision trees to extrapolate the potential value of 3DGA in decision making for targeted intervention in this population. Results Participants with SCD generally walked at a reduced gait speed. When grouped by neurological level, the tetraplegia group had a significantly lower GPS, but no specific gait patterns emerged. Participants were primarily referred to the CGAS to direct clinical intervention decisions. The most frequent recommendation following 3DGA was the prescription of an ankle foot orthosis and in some cases, the recommendation was incongruent with the referrer’s proposed intervention. Significance 3DGA can provide specific guidance in management plans for gait of patients with incomplete SCD and may help to avoid inappropriate or unnecessary interventions. This sample of patients referred to the CGAS demonstrates its clinical utility in guiding clinicians in their decision making to target individualised intervention.

High-impact physical activity has a positive influence on bone health in humans. High-impact activity generates significant ground reaction forces (GRFs) between the plantar surface of the foot and the ground surface. However, the methods of assessment of plantar GRF are limited outside of a laboratory setting. We present a wearable device featuring force sensor resistors placed on the plantar surface of the foot which may present a feasible alternative to current laboratory technology. This paper presents the design, development, and validation of such a wearable system for the assessment of plantar GRF during various forms of physical activity. GRF estimates from the wearable device were moderately correlated with the gold-standard technology during physical activity, yet estimates during walking were highly variable. Future work should be directed toward individual anatomical site analysis to increase the accuracy of force estimates in a wider range of dynamic activities while also optimizing wearability of the system.

Biomechanical data in cerebral palsy are inherently variable but no optimal model of translational joint constraint has been identified. The primary aim of this study was to determine which model of translational joint constraint resulted in the lowest within-participant variability of lower limb joint angles and moments. The secondary aim was to determine which model best distinguished known functional groups in Cerebral Palsy.Three models (three degrees of freedom, six degrees of freedom and six degrees of freedom with specified joint translation constraint) were applied to data from running trials of 40 children with cerebral palsy.Joint angle standard deviations were largest using the six degrees of freedom model and smallest using the constrained six degrees of freedom model (p 0.050). For all joints in all planes of motion, joint moment standard deviations were largest using the six degrees of freedom model and smallest using the constrained six degrees of freedom model; standard deviations using the constrained model were smaller than the three degrees of freedom model by 10-30% of moment magnitude (0.01-0.03 Nm/kg; p 0.001). The six degrees of freedom models distinguished functional subgroups with larger effect size than the three degrees of freedom model only for hip power generation in swing.A model with specified joint constraint minimized within-participant variability during running and was useful for detecting differences in functional capacity in cerebral palsy.

ObjectiveTo identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA) we administered a battery of potential measures three times over a 12-month period.MethodsSixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, six months and 12 months. Outcomes included: GAITRite® spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25 Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups.ResultsSenseWear Armband daily step count had the largest effect size of all the variables over six months (SRM=-0.615), while the PST medial-lateral index had the largest effect size (SRM=0.829) over 12 months. The FARS USS (SRM=0.824) and BBS (SRM=-0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of −2.59 (95% CI −3.52 to −1.66, pConclusionsThe FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

A neural network nonlinear regression algorithm is developed for retrieving ocean surface wind speed from the Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) lidar measurements. The neural network is trained with CALIPSO ocean surface and atmospheric backscatter measurements together with collocated Advanced Microwave Scanning Radiometer for EOS (AMSR-E) ocean surface wind speed. Ocean surface wind speeds are derived by applying the neural network algorithm to CALIPSO measurements between 2008 and 2020. CALIPSO wind speed measurements of 2015 are also compared with Advanced Microwave Scanning Radiometer 2 (AMSR-2) measurements on the Global Change Observation Mission–Water “Shizuku” (GCOM-W) satellite. Aerosol optical depths are then derived from CALIPSO’s ocean surface backscatter signal and theoretical ocean surface reflectance calculated from CALIPSO wind speed and Cox-Munk wind–surface slope variance relation. This CALIPSO wind speed retrieval technique is an improvement from our previous studies, as it can be applied to most clear skies with optical depths up to 1.5 without making assumptions about aerosol lidar ratio.

Background Non adherence is common in difficult-to-control asthma, and can be identified using 7-day FeNO suppression testing where patients take additional fluticasone via Diskus™(Accuhaler) with an INCA™electronic monitoring device attached, and self-measure FeNO at home. However, this is inconvenient for patients attending a tertiary centre and limited by FeNO meter availability. It is not known if this approach alters clinical outcomes. Objectives and Methods To examine patient acceptability and the effectiveness of replacing usual combination inhaled corticosteroid (ICS)/long-acting b2-agonist (LABA) therapy with a fluticasone/salmeterol Diskus 500+INCA for 28 days, compared to the 7-day FeNO suppression test. Secondly, to explore the clinical outcomes of patients who have undertaken INCA monitoring. Results Twenty one of 23 subjects offered replacement of their usual ICS/LABA with fluticasone/salmeterol+ INCA accepted and completed 28 days of monitoring. Fourteen (66.6%) patients reduced their FeNO by >42% (FeNO suppressors), accompanied by improvements in FEV1, ACQ and blood eosinophils, similar to the 7-day test (n=74). At 1 year, 33.9% of FeNO suppressors progressed to treatment with a biologic therapy, compared to 72.7% of non suppressors (p=0.0005). FeNO suppressor patients taking maintenance prednisolone (n=13) reduced the median baseline dose from 10 mg to 3 mg, with further reductions limited by adrenal suppression. Conclusion Replacing existing inhaled therapy with fluticasone/salmeterol+INCA for at least 28 days is acceptable to the majority of patients with difficult-to-control asthma, and identifies prior medication non adherence. INCA monitoring coupled with clinical support potentially improves patient adherence and asthma control, and prevents unnecessary progression to biological therapy.

Background: In the UK, the criteria to withdraw mepolizumab therapy from patients with severe eosinophilic asthma include failure to achieve 50% reduction in exacerbation rate or a clinically important reduction in maintenance oral corticosteroids. Aim: To characterise the patients who failed to continue receiving mepolizumab Methods: Retrospective review of a clinical database and case notes for patients who received mepolizumab in Glenfield hospital, Leicester UK, between May 2017 to Feb 2020. Results: 21 out of a total 94 patients with severe eosinophilic asthma who received mepolizumab during the study period, had treatment stopped, the causes are listed in table 1. From the group considered to have failed mepolizumab therapy, 4/15 patients had underlying immunodeficiencies including common variable immune deficiency and specific antibody deficiency that required regular immunoglobulin therapy, 2/15 with bronchiectasis and recurrent bronchitis initiating prophylaxis Azithromycin therapy and 3/15 patients who requested treatment withdrawal due to lack of perceived benefits. The remaining 6/15 patients were deemed by the MDT to have failed mepolizumab therapy without a defined cause. Conclusion: Treatment failure with mepolizumab may be secondary to exacerbation events that are driven by infection, necessitating the need to characterise exacerbations carefully prior to initiating type-2 monoclonals in severe asthma.

A high proportion of children with Attention Deficit Hyperactivity Disorder- Combined type (ADHD-CT) experience sleep and motor problems. This study investigated (a) whether motor proficiency moderated the relationship between ADHD symptoms and sleep problems in children with and without ADHD-CT and (b) whether this moderation differed as a function of ADHD diagnosis.A sample of 70 primary school male children between 8-15 years were recruited; children with ADHD-CT (n = 38; mean age 10 years, 2 months [SD = 1 year, 6 months]) and a typically developing (TD) (n = 32; mean age 9 years, 6 months [SD = 1 year, 5 months]) group.Motor proficiency was measured using the Movement Assessment Battery for Children-2nd Edition (MABC-2), ADHD symptoms were measured using the Conners' Parent Rating Scale (CPRS) and parent reported sleep problems were measured using the Children's Sleep Habits Questionnaire (CSHQ).Children who reported higher ADHD symptoms and lower motor proficiency scores reported more sleep problems. The moderation effect only held in children with a diagnosis of ADHD-CT and not in the typically developing group.These findings indicate that children who experience greater severity of ADHD symptoms who also have lower motor proficiency may be at increased risk of experiencing sleep problems. These findings also illustrate the importance of considering motor proficiency when exploring risk factors for sleep problems in children with ADHD-CT as well as sleep interventions.

Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia. This systematic review aimed for the first time to evaluate the psychometric properties of gait and walking outcomes applicable to individuals with cerebellar ataxia. Only studies evaluating straight walking were included. A comprehensive search of three databases (MEDLINE, CINAHL and EMBASE) identified 53 studies meeting inclusion criteria. Forty-nine were rated as 'poor' as assessed by the COnsensus-based Standards for the selection of health Measurement INstruments checklist. The primary objective of most studies was to explore changes in gait related to ataxia, rather than to examine psychometric properties of outcomes. This resulted in methodologies not specific for psychometric assessment. Thirty-nine studies examined validity, 11 examined responsiveness and 12 measured reliability. Review of the data identified double and single support and swing percentage of the gait cycle, velocity, step length and the Scale for Assessment and Rating of Ataxia (SARA) gait item as the most valid and responsive measures of gait in cerebellar ataxia. However, further evaluation to establish their reliability and applicability for use in clinical trials is clearly warranted. We recommend that inter-session reliability of gait outcomes should be evaluated to ensure changes are reflective of intervention effectiveness in cerebellar ataxia.

Many oil paintings, dating from the 15th century to the present, are affected by the formation of heavy-metal carboxylates (soaps) that alter the structural integrity and appearance of the works. Through transport phenomena not yet understood, free fatty acids formed from oils used as binders migrate through the paint film and react with heavy-metal ions that are constituents of pigments and/or driers, forming metal carboxylates. The local molecular dynamics of fatty acids and metal carboxylates are factors influencing material transport in these systems. We report temperature-dependent 2H NMR spectra of palmitic acid and lead palmitate as pure materials, in cross-linked linseed oil films, and in a lead white linseed oil paint film as part of our broader research into metal soap formation. Local dynamics at the α carbon, at the terminal methyl group, and at the middle of the fatty acid chain were observed in specifically deuterated materials. Changes in the dynamic behavior with temperature were observed by the appearance of two species, a solid-like material and a liquid-like material. The relative amounts of the two phases and their deuterium NMR parameters indicate that the amount of liquid-like material and the local dynamics at that site increase with temperature. At the three locations along the chain and at all temperatures, there is a larger percentage of acyl chains of both palmitic acid and lead palmitate that are "mobile" or liquid-like in linseed oil films than there are in the pure materials. However, the percentage of liquid-like species is decreased in a lead white paint film, as compared to a linseed oil matrix. In addition, these experiments indicate that there is a larger percentage of liquid-like acyl chains of palmitic acid than of lead palmitate under identical conditions in these model paint systems.

Background Older adults seek health-related information through casual internet searches. Yet, researchers focus on peer-reviewed journals and conference presentations as primary dissemination strategies. Representatives of mass media are alerted (passive diffusion) of new studies or recommendations, but the veracity of the information shared is not often analyzed, and when it is, the analysis is often not comprehensive. However, most older adults do not have access to peer-reviewed journal articles or paid subscription services for more reputable media outlets. Objective We aimed to determine what information was readily available (ie, open access) to older adults who may casually search the internet for physical activity recommendations. Methods We performed a 6-part scoping review to determine the research question and available evidence, and extract data within open-access top hits using popular online search engines. Results were categorized by a dissemination model that has categories of sources, channels, audience, and messages. Results After the iterative search process, 92 unique articles were included and coded. Only 5 (5%) cited physical activity guidelines, and most were coded as promoting healthy aging (82/92, 89%) and positive framing (84/92, 91%). Most articles were posed as educational, but the authors’ credentials were rarely reported (ie, 22% of the time). Muscle strengthening and balance components of the physical activity guidelines for older adults were rarely reported (72/92, 78% and 80/92, 87%, respectively) or inaccurately reported (3/92, 3% and 3/92, 3%, respectively). Conclusions Inconsistent messages lead to mistrust of science and public health representatives. This work highlights the lack of evidence within existing open-access resources. Further efforts are needed to ensure evidence-based public health messages are in the sources and channels older adults are using to inform their knowledge and behaviors.

Physical therapists provide important services for improving health and function for the general population; however, physical therapy (PT) is infrequently accessed by persons with a primary diagnosis of severe mental illness (SMI). This study examined the attitudes of PT students before and during their participation in a service-learning (SL) program for people with SMI.A cross-sectional institutional review board approved qualitative study collected 1-h semi-structured qualitative interviews from seven graduates of a doctor of PT program. Participants were from a New Jersey University program in the USA who participated in an SMI SL experience. Participants were asked about participant attitudes toward people with SMI and their observations during a SL experience using an interview guide. All interviews were digitally recorded, transcribed, and coded using interpretive phenomenological analysis by a team of researchers. This type of qualitative analysis aims to explore participants understanding of their experience without pre-conceived theoretical direction. Recordings, transcripts, and field notes were reviewed for recurring ideas that were summarized into codes. Through independent coding, reflexivity memos, and consensus meetings, data were further analyzed to identify themes. Investigator triangulation addressed differences and aided consensus development.Before the SL experience, the students reported negative perceptions about people with SMI and feelings of uncertainty and unpreparedness to work with this population. According to student reports, SL supported their personal and professional development and allowed them to see that PT services are beneficial for people with SMI.The results of this study indicate that PT students have negative attitudes of people with SMI and feel unprepared to work with this population. The results also support SL as an effective strategy for helping students in their preparation for working with people with SMI.

There is increasing concern over the inappropriate prescribing of inhaled corticosteroids for patients with COPD. Here the authors discuss how to step down ICS treatment without adverse effects. By James Chalmers, Alex Bobak, Jane Scullion, and Anna Murphy Inhaled corticosteroids (ICS) are frequently inappropriately prescribed for patients with COPD resulting in up to 70% of patients in current practice receiving them. ICS (prescribed as a combination inhaler with a long-acting beta2-agonist (LABA)) are primarily indicated for patients with an FEV1 Withdrawal of ICS in these patients may therefore promote cost-effective prescribing, and reduce the risk of adverse effects. Nevertheless, in the absence of recognised national guidelines, removing a longstanding therapy from patients with COPD can be challenging. Concerns and barriers reported by clinicians include the risk that patients may subsequently exacerbate or experience a worsening of symptoms, the risk of inadvertently removing ICS from patients with a diagnosis of asthma, and the risks of adrenal insufficiency. Recent randomised controlled trials clearly demonstrate it is possible to remove ICS in a subgroup of patients with COPD and replace with bronchodilator therapies, and that such withdrawal does not result in clinically important increases in exacerbations or worsening of symptoms. In this article, we provide practical advice about when and how to withdraw ICS in patients with COPD.

Introduction and objectives Currently three main classes of biologics are licensed for severe asthma treatment in the UK. These classes target IgE (omalizumab) and IL-5/IL-5R (mepolizumab/reslizumab and benralizumab). The stratification factors that identify response to omalizumab and mepolizumab beyond the licensing criteria are poorly understood in clinical practice. However, the GINA 2019 severe asthma guidelines advocate clinical stratification when >1 biologic choice exists. The study aim was to evaluate the clinical characteristics that can predict response to omalizumab and mepolizumab. Methods Over a prospective period (April 2017 to July 2019) we evaluated 105 patients initiated on biologic treatment (omalizumab n=27 [GINA 4=9, GINA 5=18 (oral corticosteroids (OCS) median (IQR):10 mg (10–15) and mepolizumab n=78 (GINA 4=13, GINA 5=65 (OCS:12.5 mg (10–15)] at a single severe asthma centre. Omalizumab response was assessed at 16 weeks as per NICE recommendations, and on-going response at one year; according to MDT defined response markers. Mepolizumab response was assessed based on NICE criteria at 1 year. We looked at the GINA 2019 treatment selection criteria (omalizumab: blood eosinophils ≥260 cells/µl, FeNO ≥20ppb, childhood-onset asthma and mepolizumab: higher blood eosinophils, more exacerbations in the previous year, adult-onset asthma (≥18 years), nasal polyposis) as baseline stratifiers of early and 1 year response using Receiver operator curve analyses (ROC). Results 35% of patients were eligible for both biologics based on baseline characteristics. When assessing response to biologics [R+ (responder)/R- (non-responder)]: we identified for omalizumab 80.8%/19.2% (16 weeks), 69.2%/30.8% (1 year) response rates and mepolizumab: 71.8%/21.2% (16 weeks), 75.9%/24.1% (1 year) response rates. None of the GINA 2019 baseline stratifiers were predictive of treatment response. The best predictor of response to omalizumab (AUC:0.810,p=0.054) and mepolizumab (AUC:0.746,p=0.006) was exacerbations in the previous year. Conclusions We have identified that >1:3 patients are eligible for more than one class of biologic. Treatment failure rates in this highly refractory population at 1 year were relatively high with between 20–30% of patients failing therapy. Only exacerbations in the previous year was a significant predictor of treatment response to both biologics. Therefore, more effective decision support tools are required to guide biologic prescribing in clinical practice.

Interprofessional attitudes existing between healthcare disciplines can negatively impact communication and collaboration in the clinical setting. While human anatomy is a topic central to healthcare trainees, the potential of the anatomy laboratory to minimize negative interprofessional attitudes has yet to be characterized. This study aimed to assess the effects of an anatomy interprofessional near-peer learning activity (AIP-NPLA) on medical and nursing students' interprofessional attitudes at McGill University. The authors employed a convergent parallel mixed methods study to explore participants' AIP-NPLA experiences. The Attitudes to Health Professionals Questionnaire (AHPQ) was used pre- and post-AIP-NPLA to assess participants' attitudes toward their own and their counterpart profession. In addition, a focus group was held immediately following the AIP-NPLA to explore participants' experiences and interprofessional perceptions. Quantitative results using a principal components analysis demonstrated significant changes in nursing students' responses between pre- and post-AIP-NPLA scoring, rating the medical profession as being more caring overall. Medical students' responses pre- and post-AIP-NPLA demonstrated no significant differences. Qualitative results also suggested a breakdown of negative attitudes, an increased understanding of inter- and intra-professional roles, and the importance of interprofessional collaboration and mutual learning for their careers. These findings revealed that attitudes among healthcare trainees may be positively restructured in the anatomy laboratory, allowing for collaborative care to predominate in current and future clinical practices.

Inhaled corticosteroids (ICS) are the core component of asthma treatment and the only maintenance therapy known to prevent asthma death. There is currently no evidence that biologics prevent asthma death in people with asthma, and as such, biologics cannot be recommended as an alternative to ICS therapy. Taking the time to assess adherence and provide interventions and education to support patients in asthma self-management has been shown to improve patient outcomes. It is therefore our responsibility as healthcare professionals to ensure that patients are supported, educated and motivated to adhere to ICS therapy before progressing to biologic therapies., ICS save lives. It is therefore our responsibility as healthcare professionals to ensure that patients are supported, educated and motivated to improve poor ICS adherence before treatment is further escalated to biologic therapy. https://bit.ly/3o2q26i

Background Nonadherence in difficult-to-control asthma can be identified using 7-day FeNO suppression testing where patients take additional fluticasone via Diskus with an Inhaler Compliance Assessment (INCA) acoustic monitoring device attached, and self-measure FeNO at home. However, this is inconvenient for patients attending a tertiary center and limited by FeNO meter availability. It is not known if this approach alters clinical outcomes. Objectives To examine patient acceptability and the effectiveness of replacing usual combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy with a fluticasone/salmeterol Diskus 500+INCA for 28 days as the initial intervention, compared with the 7-day FeNO suppression test, and to explore clinical outcomes after INCA monitoring. Methods A service evaluation of FeNO suppression testing was undertaken in clinical practice. Results Twenty-one of 23 subjects offered replacement of their usual ICS/LABA with fluticasone/salmeterol+INCA as the initial intervention accepted and completed 28 days of monitoring. Fourteen (66.6%) patients reduced their FeNO by >42% (FeNO suppressors), accompanied by improvements in forced expiratory volume in 1 second, Asthma Control Questionnaire, and blood eosinophils, similar to the 7-day test (n = 74). Twenty-two of 62 (35.5%) FeNO suppressors progressed to biological therapy, compared with 24 of 33 (72.7%) nonsuppressors (P = .0006). FeNO suppressors taking maintenance prednisolone (n = 13) who did not receive biological therapy reduced the median baseline dose from 10 to 3 mg, with further reductions limited by adrenal suppression. Conclusion Replacing existing inhaled therapy with fluticasone/salmeterol+INCA for 28 days is acceptable to the majority of people with difficult-to-control asthma and identifies prior medication nonadherence. INCA monitoring coupled with clinical support potentially improves patient adherence and asthma control, preventing unnecessary progression to biological therapy.

Dynamic nuclear polarization (DNP) is used to enhance the (ultra)wideline 207Pb solid-state NMR spectra of lead compounds of relevance in the preservation of cultural heritage objects. The DNP SSNMR experiments enabled, for the first time, the detection of the basic lead carbonate phase of the lead white pigment by 207Pb SSNMR spectroscopy. Variable-temperature experiments revealed that the short T'2 relaxation time of the basic lead carbonate phase hinders the acquisition of the NMR signal at room temperature. We additionally observe that the DNP enhancement is twice as large for lead palmitate (a lead soap, which is a degradation product implicated in the visible deterioration of lead-based oil paintings), than it is for the basic lead carbonate. This enhancement has allowed us to detect the formation of a lead soap in an aged paint film by 207Pb SSNMR spectroscopy; which may aid in the detection of deterioration products in smaller samples removed from works of art.

There is a concerted research effort to investigate brain mechanisms underlying addiction processes that may predicate the development of new compounds for treating addiction. One target is the brain's opioid system, because of its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of the mu opioid receptor (MOR) in fronto-striatal regions that predict drug relapse, and demonstrate disturbances in these regions during the processing of non-drug rewards. Naltrexone is currently licensed for alcohol and opiate dependence, and may remediate such disturbances through the blockade of MORs in fronto-striatal reward circuitry. Therefore, we examined the potential acute modulating effects of naltrexone on the anticipation of, and instrumental responding for, non-drug rewards in long-term abstinent alcoholics, alcoholic poly substance-dependent individuals and controls using a monetary incentive delay (MID) task during a randomized double blind placebo controlled functional MRI study. We report that the alcoholic poly substance-dependent group exhibited slower and less accurate instrumental responding compared to alcoholics and controls that was less evident after acute naltrexone treatment. However, naltrexone treatment was unable to remediate disturbances within fronto-striatal regions during reward anticipation and ‘missed’ rewards in either substance-dependent group. While we have not been able to identify the underlying neural mechanisms for improvement observed with naltrexone in the alcoholic poly-substance dependent group, we can confirm that both substance-dependent groups exhibit substantial neural deficits during an MID task, despite being in long-term abstinence.

Human dwelling in cities produces traces in outdoor spaces, particularly in residential neighborhoods. An essential part of dwelling is acting on one’s environment, establishing meaning and identity. These processes are challenged in cities by diversity, vying uses, and various regulations. This article suggests that expressing and encountering otherness in urban space extends through the material traces left by spatial users, communicating social information. Drawing empirically upon actor network theory’s relational approach of association, three studies are used to demonstrate that traces are important in urban space due to what they impart regarding user intentions, local interpretations, physical possibilities, and controls. Comparing traces found in three differently managed cases, the study opens up the question of how regulation and thorough upkeep may affect the expression of diversity in urban residential spaces.

Objectives: There is no medical test for autism spectrum disorder (ASD), a heterogeneous condition currently defined in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by dysfunction in social, communication, and behavioural dimensions. There is agreement in the literature that the motor profile of ASD may hold the key to improving clinical and diagnostic definition, with DSM-5 now referring to motor deficits, including “odd gait” (p. 55), as part of the ASD clinical description. This review describes the history of motor impairment in ASD, types of motor problems, and age-related motor findings and highlights evidence gaps and future research. Method: A narrative review is provided of the research literature describing motor impairment in ASD and its ability to differentiate between ASD versus non-ASD cohorts. Results: Findings show differences in motor development in children with ASD from infancy onwards, including difficulties across motor coordination, arm movements, gait, and postural stability. Motor disturbance may appear in young children with ASD prior to social and language difficulties becoming clinically apparent. However, challenges remain in defining and measuring the early motor profile that is specific to ASD. Despite well-established motor impairments in ASD, there is a lack of evidence regarding which motor-based interventions will be effective in this group. Conclusions: Motor impairment holds promise as an early diagnostic sign, a behavioural marker, and a means by which to improve identification and possibly phenotypic delineation in ASD. Further research is required to determine whether motor abnormalities can sensitively differentiate ASD from other developmental conditions and to establish evidenced-based interventions to reduce the associated impairment.

Place-keeping urges design and management professionals to collaborate towards sustaining quality places for users. However, local life, maintenance and contextual aspects contribute to places changing in unexpected manners. The current place-keeping conceptualisation focuses on the organisations behind space provision and management, leaving a knowledge gap in tying their work to the material dynamics of places’ built environments. This article translates the Actor Network Theory (ANT) approach to analyse formal and informal built environment changes, seeking to understand specific actors that affect change in an environment beyond formal institutions. The approach focuses upon the action mechanisms behind, contributing to and preventing specific material changes, holding the potential to reflectively inform practice. A case excerpt is analysed to illustrate the proposed ANT methodology. It reconstructs the changes to a hedge line and related repercussions upon the life and management of an urban residential space in Oslo. The analysis demonstrates how maintenance, use and material adjacencies affect built environment change, together with how relationships to external agendas, adjacent programming, municipal budgeting and climatic forces can limit spatial management’s response capabilities. The ANT approach can contribute the following to place evaluation and place-keeping thought: • Understanding change in the built environment as the output of multiple, heterogeneous factors; • Recognizing that intentional and unintentional actions contribute to place changes; • Tracing place dynamics across established boundaries of discipline, property and responsibility; • Re-conceptualizing place-keeping based on the mechanisms that a place’s perceivable, material quality. This article offers a perspective of understanding place use and spatial management work through the mitigating agency materials have upon practice. Offering an adaptable framework for reflective place evaluation and a material-focused re-conceptualisation of place-keeping, this article encourages relational research into the mechanisms that link spatial management and use dynamics.

The cerebellum appears to play a key role in the development of internal rules that allow fast, predictive adjustments to novel stimuli. This is crucial for adaptive motor processes, such as those involved in walking, where cerebellar dysfunction has been found to increase variability in gait parameters. Motor adaptation is a process that results in a progressive reduction in errors as movements are adjusted to meet demands, and within the cerebellum, this seems to be localised primarily within the right hemisphere. To examine the role of the right cerebellar hemisphere in adaptive gait, cathodal transcranial direct current stimulation (tDCS) was administered to the right cerebellar hemisphere of 14 healthy adults in a randomised, double-blind, crossover study. Adaptation to a series of distinct spatial and temporal templates was assessed across tDCS condition via a pressure-sensitive gait mat (ProtoKinetics Zeno walkway), on which participants walked with an induced 'limp' at a non-preferred pace. Variability was assessed across key spatial-temporal gait parameters. It was hypothesised that cathodal tDCS to the right cerebellar hemisphere would disrupt adaptation to the templates, reflected in a failure to reduce variability following stimulation. In partial support, adaptation was disrupted following tDCS on one of the four spatial-temporal templates used. However, there was no evidence for general effects on either the spatial or temporal domain. This suggests, under specific conditions, a coupling of spatial and temporal processing in the right cerebellar hemisphere and highlights the potential importance of task complexity in cerebellar function.

A complete cytotoxic profile of exposure to silver (AgNP) nanoparticles investigating their biological effects on the innate immune response of circulating white blood cells is required to form a complete understanding of the risk posed. This was explored by measuring AgNP-stimulated gene expression of the pro-inflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in THP-1 monocytes. A further study, on human monocytes extracted from a cohort of blood samples, was carried out to compare with the AgNP immune response in THP-1 cells along with the detection of pro-IL-1β which is a key mediator of the inflammasome complex. The aims of the study were to clearly demonstrate that AgNP can significantly up-regulate pro-inflammatory cytokine gene expression of IL-1, IL-6 and TNF-α in both THP-1 cells and primary blood monocytes thus indicating a rapid response to AgNP in circulation. Furthermore, a role for the inflammasome in AgNP response was indicated by pro-IL-1β cleavage and release. These results highlight the potential inflammatory effects of AgNP exposure and the responses evoked should be considered with respect to the potential harm that exposure may cause. Copyright © 2016 John Wiley & Sons, Ltd.

The use of oral methotrexate for refractory eosinophilic asthma in a tertiary asthma referral centre, Glenfield Hospital, Leicester, was evaluated between January 2006 and December 2014. The patients ( n = 61) were carefully phenotyped at baseline with markers of airway inflammation. In addition, a structured oral methotrexate proforma was utilized to evaluate response to therapy and adverse events. Oral steroid withdrawal was attempted 3 months after commencing treatment. Several outcomes were evaluated at 12 months, including both efficacy and adverse effects; 15% ( n = 9/61) responded by achieving a decrease in daily oral corticosteroid dose (mean 8.43 (±8.76) mg), although we were unable to identify factors that predicted a treatment response. There were no other significant changes in any other clinical outcome measures. There was a high rate of adverse events (19/61 (31%)), primarily gastrointestinal/hepatitis. Our findings support the use of biological agents in preference to using oral methotrexate as a steroid sparing agent at the first instance. In the event of failure of these agents, oral methotrexate remains a therapeutic option, which can be considered in highly specialist severe asthma centres.

Parasite-released extracellular vesicles (EVs) deliver signals to the host immune system that are critical to maintaining the long-term relationship between parasite and host. In the present study, total EVs (FhEVs) released in vitro by adults of the helminth parasite Fasciola hepatica were isolated using a recently described gravity flow method that protects their structural integrity. The FhEVs molecular cargo was defined using proteomic analysis and their surface topology characterised by glycan microarrays. The proteomic analysis identified 618 proteins, 121 of which contained putative N-linked glycosylation sites while 132 proteins contained putative O-linked glycosylation sites. Glycan arrays revealed surface-exposed glycans with a high affinity for mannose-binding lectins indicating the predominance of oligo mannose-rich glycoproteins, as well as other glycans with a high affinity for complex-type N-glycans. When added to bone-marrow derived dendritic cells isolated FhEV induced a novel phenotype that was categorised by the secretion of low levels of TNF, enhanced expression of cell surface markers (CD80, CD86, CD40, OX40L, and SIGNR1) and elevation of intracellular markers (SOCS1 and SOCS3). When FhEV-stimulated BMDCs were introduced into OT-II mice by adoptive transfer, IL-2 secretion from skin draining lymph nodes and spleen cells was inhibited in response to both specific and non-specific antigen stimulation. Immunisation of mice with a suspension of FhEV did not elicit significant immune responses; however, in the presence of alum, FhEVs induced a mixed Th1/Th2 immune response with high antigen specific antibody titres. Thus, we have demonstrated that FhEVs induce a unique phentotype in DC capable of suppressing IL-2 secretion from T-cells. Our studies add to the growing immuno-proteomic database that will be an important source for the discovery of future parasite vaccines and immunotherapeutic biologicals., Author summary Parasite-released extracellular vesicles (EVs) deliver signals to the host immune system that are critical to maintaining the long-term relationship between parasite and host. This study isolated total EVs (FhEVs) released in vitro by the adult stages of the parasitic worm Fasciola hepatica using a gravity flow method that protects the structural integrity of the vesicles. Proteomic analysis identified 618 proteins, 121 of which contained putative N-linked glycosylation sites while 132 proteins contained putative O-linked glycosylation sites while glycan arrays revealed surface-exposed glycans were predominantly oligo mannose-rich glycoproteins, and glycans with a high affinity for complex-type N-glycans. Since the EV molecular cargo can influence host immune cells, FhEVs were added to bone-marrow derived dendritic cells, inducing a novel cell phenotype that when adoptive transferred into OT-II mice inhibited IL-2 secretion from skin draining lymph nodes and spleen cells. Immunisation of mice with FhEV did not elicit significant immune responses; however, in the presence of alum, FhEVs induced a mixed Th1/Th2 immune response with high antigen specific antibody titres. This studied sheds like on the biological activity of FhEVs and added to the growing immuno-proteomic database that will be an important source for the discovery of future therapeutics.

To understand the mechanisms and factors that trigger soap formation and the dynamics of the reactive compounds in paints, advanced nuclear magnetic resonance (NMR) and X-ray analyses, complemented by analysis with FTIR spectroscopy, were performed on a series of lead carboxylates and model paint samples. Similar spectroscopy and lead coordination were observed for lead carboxylates of carbon chain length of 9 to 11 and 16 (palmitic acid) and 18 (stearic acid). Experiments as a function of temperature and humidity provided insight into the factors that increase soap formation. The local dynamics of palmitic acid and lead palmitate, in a linseed oil matrix at different temperatures (T) were measured by 2H NMR spectroscopy. The results show the extent of mobility of palmitic acid and lead palmitate in the paint matrix, how they differ, and how they depend on T. The kinetics of soap formation in model paint films subjected to different relative humidities was monitored by 13C NMR spectroscopy; the rate of soap formation increases with relative humidity. The results are discussed in the context of their implications for the conservation and preservation of works of art affected by lead soap formation.

BACKGROUND AND OBJECTIVE We investigated the repeatability and validity of the incremental shuttle walk test (ISWT) distance compared to peak oxygen uptake (VO2pk ) during maximal incremental cycle ergometer (ICE) and treadmill (ITM) tests in adults with severe asthma. METHODS Adults with severe asthma, Medical Research Council (MRC) dyspnoea ≥2, were recruited from specialists caring for patients with severe asthma. All participants performed three ISWT (familiarization and two subsequent tests on the same day), an ICE and an ITM in a randomized order, on separate days, to intolerance with expiratory gas analysis. RESULTS A total of 50 patients (32 females, mean (SD), age: 54 (13) years, forced expiratory volume in 1 s (FEV1 ): 1.9 (0.8) L and body mass index (BMI): 32 (6) kg/m2 ) completed all five tests. The mean (SD) ISWT distance for each test was 400 (156), 418 (142) and 438 (157) m (P = 0.001), respectively. There was a strong correlation between the ISWT distance with VO2pk derived from ITM (r = 0.74, P < 0.001) and ICE (r = 0.75, P < 0.001). CONCLUSION There was a small increase in the mean ISWT distance on sequential testing. In clinical practice, the coefficient of repeatability and heteroscedasticity need to be considered when assessing whether a true change has occurred within an individual patient. The ISWT has validity compared to VO2pk on both ICE and ITM, but they are not interchangeable.

Introduction: As part of a feasibility study, we investigated the effect of asthma-tailored pulmonary rehabilitation (AT-PR) versus usual care (UC) on exercise performance, asthma control and airway inflammation in patients with severe asthma. Methods: Patients with severe asthma were recruited and randomised 2:1 to AT-PR or UC. AT-PR involved 12 weeks of high intensity aerobic and strength training. Outcome measures included the incremental shuttle walk test (ISWT), the asthma control questionnaire (ACQ) and airway inflammation (sputum eosinophil count and fractional exhaled nitric oxide [FeNO]). Analysis of covariance was used to compare the between group difference (AT-PR - UC). Results: 51 patients (34 females, mean [SD] age 54 [14] yr, BMI 32 [6] kg/m2, FEV1 1.91 [0.78] L, FEV1/FVC 68 [11] %, ISWT 452 [158] m, ACQ 1.98 [0.9], FeNO 34 [29] ppb and median [IQR] sputum eosinophil count 0.5 [0.0 to 11.9] %) were randomised. The results of AT-PR (n=21 completers) compared to UC (n=9 completers) are shown in Table 1. There was no correlation between change in exercise performance and either asthma control -0.203, p>0.05 or airway inflammation -0.003, p>0.05. Conclusion: Our data suggests AT-PR may improve physical performance and asthma control. In this small study no effect on airway inflammation was seen and many patients had well controlled airway inflammation at baseline.

Nanotechnology is a rapidly growing field with silver nanoparticles (AgNP) in particular utilized in a wide variety of consumer products. This has presented a number of concerns relating to exposure and the associated toxicity to humans and the environment. As inhalation is the most common exposure route, this study investigates the potential toxicity of AgNP to A549 alveolar epithelial carcinoma cells and the influence of a major component of lung surfactant dipalmitoylphosphatidylcholine (DPPC) on toxicity. It was illustrated that exposure to AgNP generated low levels of oxidative stress and a reduction in cell viability. While DPPC produced no significant effect on viability studies its presence resulted in increased reactive oxygen species formation. DPPC also significantly modified the inflammatory response generated by AgNP exposure. These findings suggest a possible interaction between AgNP and DPPC causing particles to become more reactive, thus increasing oxidative insult and inflammatory response within A549 cells.

Establishing realistic exposure scenarios is critical for cytotoxic investigation of silver nanoparticles (AgNP) in the gastrointestinal tract. This study investigated the potential interaction with and effect of biofluid components, namely cholic acid, deoxycholic acid and ursodeoxycholic acid, on AgNP toxicity. Two cell lines corresponding to organs related to the biofluid components were employed. These were HepG-2 a hepatocellular carcinoma derived from liver tissue and Hep2 an epithelial cell line. Physiochemical and cytotoxic screening was performed and the ability of biofluid components to modify AgNP cytotoxicity was explored. No alteration to the physiochemical characteristics of AgNP by biofluid components was demonstrated. However, biofluid component addition resulted in alteration of AgNP toxicity. Greater reactive oxygen species induction was noted in the presence of cholic acid and deoxycholic acid. Ursodeoxycholic acid demonstrated no modification of toxicity in HepG-2 cells; however, significant modification was noted in Hep2 cells. It is concluded that biofluid components can modify AgNP toxicity but this is dependent on the biofluid component itself and the location where it acts.

Background. Falls are common and disabling in people with Parkinson’s disease (PD). There is a need to quantify the effects of movement rehabilitation on falls in PD. Objective. To evaluate 2 physical therapy interventions in reducing falls in PD. Methods. We randomized 210 people with PD to 3 groups: progressive resistance strength training coupled with falls prevention education, movement strategy training combined with falls prevention education, and life-skills information (control). All received 8 weeks of out-patient therapy once per week and a structured home program. The primary end point was the falls rate, recorded prospectively over a 12 month period, starting from the completion of the intervention. Secondary outcomes were walking speed, disability, and quality of life. Results. A total of 1547 falls were reported for the trial. The falls rate was higher in the control group compared with the groups that received strength training or strategy training. There were 193 falls for the progressive resistance strength training group, 441 for the movement strategy group and 913 for the control group. The strength training group had 84.9% fewer falls than controls (incidence rate ratio [IRR] = 0.151, 95% CI 0.071-0.322, P < .001). The movement strategy training group had 61.5% fewer falls than controls (IRR = 0.385, 95% CI 0.184-0.808, P = .012). Disability scores improved in the intervention groups following therapy while deteriorating in the control group. Conclusions. Rehabilitation combining falls prevention education with strength training or movement strategy training reduces the rate of falls in people with mild to moderately severe PD and is feasible.

The provision and administration of high quality urban public green spaces intertwines issues of planning, design, management and maintenance with governance. The benefits of such spaces are often tied to social justice, public health and recreation, biodiversity and helping cities to deal with climate change. International policies and changes in public administration have encouraged user participation across multiple phases of green space development. Although sceptics towards participation are easily found supporting arguments sometimes stand without critique, not questioning how participation affects the physical quality of green spaces. This literature review surveyed empirical scientific studies seeking to answer the following research question: How does research to date reflect over user participation's contribution to public urban green space quality? The review includes 31 articles from peer-reviewed scientific journals and finds an array of arguments used to support and attribute potential benefits to participation. However, analysing what has been empirically tested in these articles shows an even and general lack of proof for these arguments, implying that many arguments for participation are taken for granted. A particularly large disparity was found between the discussing and testing of many arguments regarding how participation may directly benefit urban green spaces. Rather than assessing the physical outputs of participation, most of the empirical studies tested process benefits to users and administrators. Due to the discovered predominance of these process-driven studies, it remains unclear whether participation actually improves green spaces, or if it is just for the benefit of the people involved. The gap in scientific knowledge found here calls for a re-focus to case level research, empirically testing where the actual benefits of participation lie and how participation processes might best lead to high quality green spaces in practice.

There remains a substantial lack of evidence to support the use of foot orthoses as a conservative treatment option for idiopathic toe walking (ITW). Encouraging heel contact during gait is one of the primary goals of most interventions in paediatric ITW.Does the combined treatment of high-top boots and orthoses increase the number of heel contacts during gait and change spatio-temporal gait parameters?This within subject designed randomised controlled trial recruited fifteen children diagnosed with ITW (n = 10 males). They were fitted with bilateral custom made rigid contoured carbon fibre foot orthoses placed inside high-top boots. To analyze the effect of this treatment, heel contacts and spatio-temporal parameters measured by an 8.3 m Gaitrite® mat were compared to barefoot walking and shod walking.An immediate increase in heel contact (p = 0.021) was observed in the combined treatment only. Gait changes included a large increase in stride time in the combined treatment condition compared to barefoot walking (p = 0.006). This was associated with a decrease in the percentage of swing phase in the gait cycle (p 0.010), an increase in stance phase (p 0.010) and an increase in double support time (p 0.001).These results suggest the hardness and thickness of the shoe and stiffness of the orthosis midsole may lead to improved local dynamic stability and foot position awareness with increased sensory feedback provided through the entire length of the foot. Further research is indicated to validate this treatment option on long term outcomes in this population group.