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Objective: Describe how people with lower limb spasticity present for treatment in routine clinical practice., Methods: Prospective, observational study (Clinicaltrials.gov: NCT04050527) of ambulatory adult patients (≥ 18 years) with unilateral lower limb spasticity (able to take ≥ 5 steps with or without assistance) presenting for routine spasticity management, including treatment with abobotulinumtoxinA., Results: The study population included 430 adults with lower limb spasticity. Despite their relatively young age (mean ± standard deviation 53.7 ± 13.9 years), only 20% of patients were employed. Most patients had an acquired brain injury due to cerebrovascular disease; 84.1% reported having concomitant upper limb spasticity. Using the Leg Activity Measure, most patients reported no or only mild difficulties in performing hygiene/positioning tasks, while 80.7% had at least mild difficulty with indoor ambulation and 90.5% had at least mild difficulty with walking outdoors. Sensory, communication and/or cognitive impairments were also common. At the first treatment cycle, 50.7% of patients set active function primary goals, including locomotion transferring or standing., Conclusion: These observations highlight the complexity of presentation that must be considered when setting treatment goals for lower limb spasticity and emphasize the types of impairment and activity (functional) limitations that treating teams may expect to encounter in their patients and should cover in their initial and follow-up assessments.

Objective: As out-of-hospital medicine evolves, emergency medical services (EMS) education practices must also be updated to ensure that EMS professionals acquire and maintain the skills needed to best serve patients. We aimed to identify and rank the top 10 research priorities related to EMS education in the United States., Methods: We conducted a convenience survey of EMS educators to identify challenges facing EMS education before leveraging a purposefully selected panel of EMS educators to prioritize research gaps through a modified Delphi approach. Data were collected electronically (March 2021-June 2021) over 4 survey rounds consisting of idea generation (Rounds 1 and 2), importance scoring (Round 3), and consensus ranking (Round 4). At the end of Round 4, composite scores were used to generate a list of 10 prioritized research gaps related to EMS education., Results: In the pre-Delphi survey, 463 EMS educators identified 2055 challenges facing EMS education. We recruited 32 EMS education experts as Delphi panelists and 28 completed all 4 rounds. Panelists submitted 77 knowledge gaps. The top 10 knowledge gaps included defining competency of EMS learners and educators, association of curricula and accreditation requirements with real-world practice, the effects of diversity and cultural humility among educators and learners on equitable patient care, evidence-based teaching methods, and public perception of the EMS profession and education system., Conclusions: Although 10 gaps were prioritized, panelists deemed all 77 gaps as having considerable importance for EMS education. This suite of knowledge gaps is intended to guide researchers and research-funding bodies for future resource allocation., Competing Interests: The authors have no conflicts of interest to report. This work was funded by the National Association of EMS Educators., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Purpose: The impact of botulinum neurotoxin-A (BoNT-A) on functional outcomes when managing focal muscle spasticity remains unclear. It is possible that randomised controlled trial (RCT) design and/or reporting may be a contributing factor. The objective of this review was to determine the extent to which RCTs evaluating functional outcomes following BoNT-A align with focal spasticity guidelines., Materials and Methods: RCTs published from 2010 were included if they targeted focal spasticity, included BoNT-A, randomised a physical intervention to the upper/lower limb, or the primary outcome(s) related to the activity/participation domains of the International Classification of Functioning, Disability, and Health. Data extraction and quality appraisal using the Modified PEDro and Modified McMasters Tool were performed independently by two reviewers. General research practices were also extracted such as compliance with therapy reporting guidelines., Results: Fifty-two RCTs were eligible. Individualised goal setting was uncommon (25%). Six studies (11.5%) included multi-disciplinary management, and five (9.6%) included patient/caregiver education. Four studies (7.7%) measured outcomes beyond 6 months. The Median Modified PEDro score was 11/15., Conclusions: Alignment with focal spasticity guidelines in RCTs was generally low. Our understanding of the impact of focal spasticity management on functional outcomes may be improved if RCT design aligned more closely with guideline recommendations.IMPLICATIONS FOR REHABILITATIONThe influence of BoNT-A on improved functional outcomes is yet to be determined.Individualised goal setting with a multi-disciplinary team is uncommon in an RCT design, despite it being a key guideline recommendation.Given the long-term nature of spasticity management, guidelines recommend short as well as long-term reviews following intervention however RCTs rarely assess beyond 6 months.

Purpose: Hemiplegic shoulder pain (HSP) is a common but heterogeneous complication of acquired brain injury. Integrated care pathways (ICPs) can support clinical decision-making, prompting timely intervention to improve quality of care. This 18-year cohort analysis of clinical data presents outcomes from an ICP for management of HSP in an inpatient rehabilitation unit., Materials & Methods: Consecutive data were extracted for all eligible patients admitted between 2000-2018 ( n  = 333). Patients were categorised according to presentation pattern ("Floppy-subluxed" (59%), "Painful-stiff" (21%) or Mixed/not categorised(20%)) to help guide early management. Pain was assessed using the Shoulder-Q with pain ratings/10 in three domains: rest, night-time and movement. Patients with pain reduction ≥3 points in any domain were designated 'responders'., Results: Mean baseline pain scores were 4.7 (95%CI 4.5,5.0). They were higher on movement (6.1(5.8,6.3)) than at rest (4.7(4.3, 5.0)) or at night (5.7(5.2,5.9)). Pain reduced significantly in all three domains ( p  < 0.0001) with a 65% overall response rate and complete resolution of pain 21-41%. There was a significant relationship between category of presentation pattern and management protocol used (X 2  = 31.2, p  < 0.0001)., Conclusion: These high pain-response rates compare favourably to the literature (14-27%), suggesting that this stratified and integrated approach to HSP guides more effective management in this heterogeneous clinical presentation.Implications for RehabilitationTwo-thirds of the patients demonstrated a clinically-significant reduction in pain when managed using the integrated care pathway. These results compare favourably with pain resolution rates of well under one-third cited in the literature and suggest that the integrated care pathway leads to reduced pain and improved patient outcomes.Hemiplegic shoulder pain can result from a range of different clinical problems. The diversity of presentation and the range of required treatments are confirmed in this 18-year cohort analysis.Heterogeneity in presentation of HSP poses a challenge for both management and the evaluation of outcome. The results of this study suggest that a stratified approach helps to guide more effective management.

Objective: Non-pharmacological adjunctive therapies can be used alongside botulinum toxin injection to enhance its efficacy. The objective of this global study was to determine the current practice and perception among clinicians of the use of adjunctive therapies after botulinum toxin injections for the treatment of limb spasticity., Methods: A questionnaire with 22 questions on clinical practice demographics, self-reported use and clinician opinion on barriers to the use of complementary therapies, and priorities for future research was translated into 7 languages and distributed worldwide through national and international professional associations concerning (neuro)rehabilitation., Results: A total of 527 clinicians from 52 countries responded to the survey. Most commonly used physical interventions were: active exercise programmes at home (81%), stretching programmes at home (81%), and splinting (70%), followed by active movement exercises (65%) and within 30 min of botulinum toxin injection and constraint induced movement therapy (63%). The main barriers reported by clinicians to provision of these interventions were clinicians' lack of time, limited financial resources, and lack of evidence. Future research should focus primarily on immediate active movement exercises and passive stretching., Conclusion: Worldwide, clinicians often recommend adjunctive therapies after a botulinum toxin injection to reduce spasticity. The most commonly used physical interventions among clinicians were active exercises at home, stretching at home, and splinting. Lack of evidence, time and financial constraints were identified as barriers to providing these interventions.

Background: Little is known about how people with multiple sclerosis (MS) and their families comprehend advance care planning (ACP) and its relevance in their lives., Aim: To explore under what situations, with whom, how, and why do people with MS and their families engage in ACP., Methods: We conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach., Results: Participants' narratives focused on three major themes: (i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals' accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate ACP-related discussions. Some shared concerns of their lack of confidence when having these discussions., Conclusion: These findings support the need for a whole system strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Advanced cancer and/or respiratory disease threaten a person's independence in activities of daily living (ADL). Understanding how disability develops can help direct appropriate and timely interventions., Aim: To identify different trajectories and associations of disability in ADL and appraise its measurement., Methods: Medline, Embase, PsychINFO, and CINAHL databases were searched for cohort studies with measures of disability in ADL in advanced cancer or respiratory disease at three or more timepoints. Data were narratively synthesized to produce a typology of disability trajectories and a model of factors and outcomes associated with increasing disability., Results: Of 5702 publications screened, 11 were included. Seventy-four disability trajectories were categorized into typologies of unchanging ( n  = 20), fluctuating ( n  = 21), and increasing disability ( n  = 33). Respiratory disease did not predict any particular disability trajectory. Advanced cancer frequently followed trajectories of increasing disability. Factors associated with increasing disability included: frailty, multi-morbidity, cognitive impairment, and infection. Increased disability led to recurrent hospital admissions, long-term care, and/or death. Methodological limitations included use of non-validated measures., Conclusions: Increasing disability trajectories in advanced cancer and/or respiratory disease is related to potentially modifiable personal and environmental factors. We recommend future studies using validated disability instruments.Implications for rehabilitationDisability in activities of daily living (ADL) is a common unmet need in advanced cancer or respiratory disease and represents an important outcome for patients, caregivers and health and social care services.Trajectories of ADL disability can be categorized into increasing, fluctuating, and unchanging disability, which could help planning of rehabilitation services in advanced cancer or respiratory disease.Increasing disability in advanced cancer or respiratory disease relates to personal and environmental factors as well as bodily impairments, which can all be modifiable by intervention.This review highlights implications for the measurement of ADL disability in advanced cancer or respiratory disease and recommends use of validated measures of ADL to understand what factors can be modified through rehabilitation interventions.

Objective: To identify and appraise the existing clinical practice guidelines, consensus statements and Cochrane systematic reviews for the management of adult and paediatric focal spasticity to generate a single synthesized guideline., Methods: Systematic review of 12 electronic databases. Clinical practice guidelines, consensus statements and Cochrane systematic reviews for focal spasticity in adults and children. Included studies were appraised according to the AGREE II criteria., Results: A total of 25 papers were included in this review, comprising 12 clinical practice guidelines, nine consensus statements and four Cochrane systematic reviews. The areas most strongly endorsed were: (1) management to be provided by a multi-disciplinary team, (2) therapy should be goal-directed, (3) goals to be developed in conjunction with the patient and family, and (4) importance of follow-up evaluations. There was a greater focus on activity outcomes and classification in the paediatric papers. The guidelines varied considerably in their quality, with AGREE II scores ranging from 52.8 to 97.1%., Conclusions: This systematic review has synthesized the key elements regarding principles of focal spasticity management, outcome measures, physical interventions and educational recommendations into a single, readily applied guideline available for clinical use. Despite considerable variability in the quality of the guidelines, several strong themes emerged.Implications for rehabilitationFocal spasticity management should be multi-disciplinary, patient-centred and goal-directed.Routine measurement of impairment and activity are strongly endorsed.Botulinum toxin A injection should only be provided as part of an integrated approach to focal spasticity management.

Objectives: Platelet activation underpins thrombus formation in ischemic stroke. The active, dimeric form of platelet receptor glycoprotein (GP) VI plays key roles by binding platelet ligands collagen and fibrin, leading to platelet activation. We investigated whether patients presenting with stroke expressed more GPVI on their platelet surface and had more active circulating platelets as measured by platelet P-selectin exposure., Methods: 129 ischemic or hemorrhagic stroke patients were recruited within 8h of symptom onset. Whole blood was analyzed for platelet-surface expression of total GPVI, GPVI-dimer, and P-selectin by flow cytometry at admission and day-90 post-stroke. Results were compared against a healthy control population (n = 301)., Results: The platelets of stroke patients expressed significantly higher total GPVI and GPVI-dimer (P<0.0001) as well as demonstrating higher resting P-selectin exposure (P<0.0001), a measure of platelet activity, compared to the control group, suggesting increased circulating platelet activation. GPVI-dimer expression was strongly correlated circulating platelet activation [r2 = 0.88, P<0.0001] in stroke patients. Furthermore, higher platelet surface GPVI expression was associated with increased stroke severity at admission. At day-90 post-stroke, GPVI-dimer expression and was further raised compared to the level at admission (P<0.0001) despite anti-thrombotic therapy. All ischemic stroke subtypes and hemorrhagic strokes expressed significantly higher GPVI-dimer compared to controls (P<0.0001)., Conclusions: Stroke patients express more GPVI-dimer on their platelet surface at presentation, lasting at least until day-90 post-stroke. Small molecule GPVI-dimer inhibitors are currently in development and the results of this study validate that GPVI-dimer as an anti-thrombotic target in ischemic stroke., Competing Interests: The authors have declared that no competing interests exist.

Objective: To describe the development of the Spasticity-related Quality of Life 6-Dimensions instrument (SQoL-6D) and its sensitivity to clinical change (responsiveness)., Design: Multicentre, prospective, longitudinal cohort study at 8 UK sites (NCT03442660)., Patients: Adults (n = 104) undergoing focal treatment of upper limb spasticity., Methods: No condition-specific health-related quality of life tool is available for upper-limb spasticity of any aetiology. The SQoL-6D was developed to fulfil this need, designed to complement the Upper Limb Spasticity Index (which incorporates the Goal Attainment Scaling evaluation of upper limb spasticity [GASeous] tool) with targeted standardised measures. The 6 dimensions of the SQoL-6D (score range 0-4) map onto common treatment goal areas identified in upper-limb spasticity studies. A Total score (0-100) provides overall spasticity-related health status. To assess responsiveness, the SQoL-6D, Global Assessment of Benefit scale and "GASeous" were administered at enrolment and 8 weeks., Results: Significant differences in mean SQoL-6D Total score change and effect sizes across patients rating "some benefit" (0.51) and "great benefit" (0.88) supported responsiveness., Conclusion: The SQoL-6D is a promising new measure of health status in upper limb spasticity, that enables systematic assessment of the impact of this condition in relation to patients' priority treatment goals. A psychometric evaluation of SQoL-6D is presented separately.

Objective: Psychometric evaluation of the Spasticity-related Quality of Life 6-Dimensions instrument (SQoL-6D)., Design: A clinimetric evaluation conducted in a multicentre, prospective, longitudinal cohort study at 8 UK sites., Patients: Adult patients (n=104) undergoing focal treatment of upper-limb spasticity., Methods: The SQoL-6D was administered in the clinic at enrolment and at 8 weeks, then 1-4 days later at home to assess test-retest reliability., Results: The SQoL-6D demonstrated adequate construct validity and unidimensionality of the scale, allowing the calculation of a Total score. Cronbach's alpha (0.74) supported the internal consistency reliability, while the intraclass correlation coefficient supported test-retest reliability (0.82). Correlation coefficients with established instruments supported convergent validity, while significant differences between known-groups (of differing clinical severity) in SQoL-6D Total score confirmed its sensitivity to both cross-sectional and longitudinal differences., Conclusion: The SQoL-6D is a promising new measure to assess health status for patients with upper-limb spasticity of any aetiology. Further investigation and exploration of the allocation of weights to convert the SQoL-6D to a health-related quality of life utility index, are required.

Background: Current practice for physical wellbeing of people in a Prolonged Disorder of Consciousness (PDOC) is variable. A scoping literature review identified no agreed standard of care for physical management of those in a PDOC. This study addressed this deficit using a consensus process applied using nominal group technique., Aim: The aims of this project were to promote best practice for physical management in PDOC, by identifying consensus for: 1) a pathway of care; and 2) current best practice recommendations., Design: A consensus process using nominal group technique., Setting: Representation from national, purposively selected, rehabilitation services assessing and managing people in a PDOC in the UK., Population: The population to whom the consensus process relates are people in a PDOC, requiring physical management., Methods: An initial meeting with selected clinical experts from national centres was conducted to set terms of reference. A consensus meeting using nominal group technique (N.=33) then followed. Experts were initially asked to review systematic review findings reproduced as statements. Following systematic refinement, they were then asked to vote on the importance and relevance of statements., Results: Following the nominal group process, 25 initial recommendations were refined to 19, which expressed the principles of physical management for people with a Prolonged Disorder of Consciousness. Statements are grouped into "acute-care" (6-recommendations), "postacute care" (10-recommendations) and "long-term care" (3-recommendations). Across the participants, agreement with the final recommendation statements ranged from 100-61% (N.=33-20), 15 of the statements were supported by 85% or more experts (N.=29). In addition, a clinical pathway of care, incorporating the recommendation principles was produced (agreement from 28 experts, 83%)., Conclusions: The recommendations provide a basis for standardising current practice. They provide a standard against which care, and effectiveness can be evaluated. An accessible guideline document is planned for publication to enable implementation into practice, supported by online resources., Clinical Rehabilitation Impact: Recommendations have been produced under the headings of "acute care," "postacute care" and "long-term care." In addition, a pathway for provision of care interventions has been identified for the physical management of people in a prolonged disorder of consciousness.

Stroke patients with spasticity usually require long-lasting care and interventions but frequently report that outpatient and community treatment is limited, reflecting a significant unmet need in health and social care provision. Rehabilitation and spasticity management services are essential for patient recovery, with improvements in both activity and participation reducing the burden on patients, family and society. Current clinical guidance provides scope for improvements in both post-stroke management and spasticity prevention. However, access to specialist services can be limited and the patient journey does not always match national recommendations. Identification of spasticity and its predictors and lack of subsequent referral to rehabilitation or specialist spasticity services are key issues in the management of post-stroke spasticity. Implementation of a traffic light classification system prioritises patients at an increased risk of spasticity and promotes early and consistent management across the spectrum of primary and secondary care. The proposed system is based on clinical evidence, expert consensus and recent clinical guidelines. It provides simple and straightforward criteria for management, multidisciplinary consultation and referral to specialist spasticity services, with patients allocated by monitoring requirements and a low (green/periodic monitoring), medium (amber/routine referral) or high risk (red/urgent referral) of spasticity., Competing Interests: Declarations of Conflicting Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Conflicting interests: GB has received educational support and honoraria from Allergan, Ipsen and Merz. GS has received Speaker fees from Bayer, BI, BMS, Covedien, Grunenthal, Medtronic, MSD and Pfizer. Advisory board fees from Allergan, Amgen, Bayer, BI and Pfizer. Travel expenses from, Bayer, BI, Medtronic, Merc, MSD and Pfizer. He has no personal financial interest in any of the material mentioned in this article. SA has a specific interest in outcomes evaluation and has published on the use of Goal Attainment Scaling in this context, as well as a number of the other standardised measures such as the Arm and Leg activity measures. All of these tools are freely available. He has received educational support and honoraria from Allergan, Ipsen and Mertz, who manufacture botulinum toxin products and has received research grants from Ipsen. He has no personal financial interest in any of the material mentioned in this article. RA has received educational support and honoraria from Allergan, and educational support from Ipsen and Mertz, who all manufacture botulinum toxin products. She has no personal financial interest in any of the material mentioned in this article. DH has contributed to Allergan, Ipsen and Merz educational materials., (© The Author(s) 2021.)

Cancer is now a leading health concern worldwide. In an effort to provide these patients with adequate care, coordination between anesthesiologists and surgeons is crucial. In cancer-related treatment, it is very clear that radio-chemotherapy and medical procedures are important. There are some obstacles to anesthesia when dealing with cancer treatment, such as physiological disturbances, tumor-related symptoms, and toxicity in traditional chemotherapy treatment. Therefore, it is important that a multisystemic, multidisciplinary and patient-centered approach is used to preserve perioperative homeostasis and immune function integrity. Adding adjuvants can help increase patient safety and satisfaction and improve clinical efficacy. Correctly paired anesthetic procedures and medications will reduce perioperative inflammatory and immune changes that could potentially contribute to improved results for future cancer patients. Further research into best practice strategies is required which will help to enhance the acute and long-term effects of cancer care in clinical practice.

Context: Managing activities of daily living is important to people with advanced cancer or chronic obstructive pulmonary disease (COPD). Understanding disability in activities of daily living may inform service planning., Objective: To identify the prevalence of disability in activities of daily living, associations and change over time, in older people with advanced cancer or COPD., Methods: Secondary analysis of International Access, Rights and Empowerment (IARE) studies in adults aged ≥65 years with advanced disease in the United Kingdom, Ireland, and United States, using cross-sectional (IARE I & II) and longitudinal (IARE II, 3 timepoints over 6 months) data. Measures included disability in activities of daily living (Barthel Index), symptom severity (Palliative Outcome Scale), and assistive device use (self-reported). Logistic regression was used to identify relationships between disability and age, sex, living alone, diagnosis, and symptom burden; visual graphical analysis explores individual disability trajectories., Results: One hundred fifty-nine participants were included (140 cancer, 19 COPD). Sixty-five percent had difficulty climbing stairs, 48% bathing, 39% dressing, and 36% mobilizing. Increased disability was independently associated with increased symptom burden (odds ratio, 1.08 [95% CI:1.02-1.15], P = 0.01) and walking unaided (z = 2.35, P = 0.02), but not with primary diagnosis (z = -0.47, P = 0.64). Disability generally increased over time but with wide interindividual variation., Conclusion: Disability in activities of daily living in advanced cancer or COPD is common, associated with increased symptom burden, and may be attenuated by use of assistive devices. Individual disability trajectories vary widely, with diverse disability profiles. Services should include rehabilitative interventions, guided by disability in individual activities of daily living., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: This study investigated the ArmA-TH sub-scale measurement properties based on item response theory using the Rasch model., Methods: Patients with upper limb hemiplegia resulting from cerebrovascular and other brain disorders were asked to complete the ArmA-TH questionnaire. Rasch analysis was performed to test how well the ArmA-TH passive and active function sub-scales fit the Rasch model by investigating unidimensionality, response category functioning, reliability of person and item, and differential item functioning (DIF) for age, sex, and education., Results: Participants had stroke or other acquired brain injury (n = 185), and the majority were men (126, 68.1 %), with a mean age of 55 (SD 22). Most patients (91, 49.2 %) had graduated from elementary/primary school. For the ArmA-TH passive function scale, all items had acceptable fit statistics. The scale's unidimensionality and local independence were supported. The reliability was acceptable. A disordered threshold was found for five items, and none indicated DIF. For the ArmA-TH active function scale, one item was misfit and three were locally dependent. The reliability was good. No items showed DIF. All items had disordered thresholds, and the data fitted the Rasch model better after rescoring., Conclusions: Both sub-scales of ArmA-TH fitted the Rasch model and were valid and reliable. The disordered thresholds should be further investigated.

Objective: To assess the longitudinal effects of integrated spasticity management incorporating repeated cycles of botulinum toxin A type A (BoNT-A) over 2 years., Methods: The Upper Limb International Spasticity study was a prospective, observational, cohort study following adult patients over 2 years of integrated upper-limb spasticity management including repeat botulinum toxin (BoNT-A) treatment (any commercially-available product)., Results: A total of 1,004 participants from 14 countries were enrolled, of which 953 underwent ≥ 1 BoNT-A injection cycle (median 4 cycles) and had ≥ 1 goal attainment scaling assessment. Most participants (55.9-64.6% across cycles 1-6) saw a therapist after BoNT-A treatment; the most frequent therapy intervention was passive stretch (70.1-79.8% across cycles 1-6). Patients achieved their goals as expected over repeated cycles; mean cumulated goal attainment scaling T-score at 2 years was 49.5 (49.1, 49.9). Mean goal attainment scaling change scores of ≥ 10 were maintained across up to 7 cycles. Higher rates of goal achievement were seen for primary goals related to passive vs active function (86.6% vs 71.4% achievement). Standardized measures of spasticity, pain, involuntary movements, active and passive function improved significantly over the study., Conclusion: This large, international study provides evidence for benefit of repeated cycles of BoNT-A, over 2 years captured through person-centred goal attainment and standardized measures.

Introduction: This systematic review appraises the measurement quality of tools which assess activity and/or participation in adults with upper limb spasticity arising from neurological impairment, including methodological quality of the psychometric studies. Differences in the measurement quality of the tools for adults with a neurological impairment, but without upper limb spasticity, is also presented., Methods: 29 measurement tools identified in a published review were appraised in this systematic review. For each identified tool, we searched 3 databases (Medline, Embase, CINAHL) to identify psychometric studies completed with neurorehabilitation samples. Methodological quality of instrument evaluations was assessed with use of the Consensus-based Standards for the Selection of Health Status Measurement Instruments (COSMIN) checklist. Synthesis of ratings allowed an overall rating of the psychometric evidence for each measurement tool to be calculated., Results: 149 articles describing the development or evaluation of psychometric properties of 22 activity and/or participation measurement tools were included. Evidence specific to tool use for adults with spasticity was identified within only 15 of the 149 articles and provided evidence for 9 measurement tools only. Overall, COSMIN appraisal highlighted a lack of evidence of measurement quality. Synthesis of ratings demonstrated all measures had psychometric weaknesses or gaps in evidence (particularly for use of tools with adults with spasticity)., Conclusions: The systematic search, appraisal and synthesis revealed that currently there is insufficient measurement quality evidence to recommend one tool over another. Notwithstanding this conclusion, newer tools specifically designed for use with people with neurological conditions who have upper limb spasticity, have emergent measurement properties that warrant further research., Systematic Review Registration: PROSPERO CRD42014013190., Competing Interests: The authors have declared that no competing interests exist.

In people with advanced respiratory disease, we examined (i) the impact of COVID-19-related physical and social isolation on physical activity and (ii) relationships between time spent in isolation and disability in activities of daily living. Cross-sectional analysis was conducted in adults with advanced non-small cell lung cancer, chronic obstructive lung disease or interstitial lung disease. Measures included change in physical activity since physically and socially isolating (Likert scale) and disability (Barthel Index and Lawton-Brody IADL scale) or difficulty (World Health Organisation Disability Assessment Schedule-2.0) in daily activities. Multiple logistic regression was used to examine factors associated with disability in daily activities. 194/201 participants were isolating for a median [IQR] 5 [3-8]-month period, often leading to lower levels of physical activity at home ( n = 94, 47%), and outside home ( n = 129, 65%). 104 (52%) and 142 (71%) were not fully independent in basic and instrumental activities of daily living, respectively. 96% reported some degree of difficulty in undertaking daily activities. Prolonged physical and social isolation related to increased disability in basic (r = -0.28, p < 0.001) and instrumental (r = -0.24, p < 0.001) activities of daily living, and greater difficulty in daily activities (r = 0.22, p = 0.002). Each month spent in physical or social isolation was independently related to disability in basic activities of daily living (odds ratio [OR], 1.17 [95% CI: 1.03-1.33], p = 0.013). These findings suggest disability in daily activities is associated with prolonged physical or social isolation, which may present as difficulty in people who are fully independent. Post-isolation recovery and rehabilitation needs should be considered for all people deemed extremely clinically vulnerable.

Background: Advance care planning (ACP) is reported to improve the quality of outcomes of care among those with life-limiting conditions. However, uptake is low among people living with multiple sclerosis (MS) and little is known about why or how people with MS engage in this process of decision-making., Aims: To develop and refine an initial theory on engagement in ACP for people with MS and to identify ways to improve its uptake for those who desire it., Methods: Realist review following published protocol and reporting following Realist and Meta-narrative Evidence Synthesis: Evolving Standards (RAMESES) guidelines. A multi-disciplinary team searched MEDLINE, PsychInfo, CINAHL, Scopus, Web of Science, Embase, Google Scholar in addition to other sources from inception to August 2019. Quantitative or qualitative studies, case reports, and opinion or discussion articles related to ACP and/or end of life discussions in the context of MS were included, as well as one article on physical disability and one on motor neuron disease, that contributed important contextual information. Researchers independently screened abstracts and extracted data from full-text articles. Using abductive and retroductive analysis, each article was examined for evidence to support or refute 'context, mechanism, and outcome' (CMO) hypotheses, using the Integrated Behaviour Model to guide theory development. Quality was assessed according to methodological rigour and relevance of evidence. Those studies providing rich descriptions were synthesised using a realist matrix to identify commonalities across CMO configurations., Results: Of the 4,034 articles identified, 33 articles were included in the synthesis that supported six CMO hypotheses that identified contexts and mechanisms underpinning engagement in ACP for people with MS and included: acceptance of their situation, prior experiences, confidence, empowerment, fear (of being a burden, of death and of dying) and the desire for autonomy. Acceptance of self as a person with a life-limiting illness was imperative as it enabled people with MS to see ACP as pertinent to them. We identified the context of MS-its long, uncertain disease trajectory with periods of stability punctuated by crisis-inhibited triggering of mechanisms. Similarly, the absence of skills and confidence in advanced communication skills among health professionals prevented possibilities for ACP discussions taking place., Conclusion: Although mechanisms are inhibited by the context of MS, health professionals can facilitate greater uptake of ACP among those people with MS who want it by developing their skills in communication, building trusting relationships, sharing accurate prognostic information and sensitively discussing death and dying., Competing Interests: The authors have declared that no competing interests exist.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered 1 . Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants 2 , we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases. In cells, we found that nuclear PHIP (pleckstrin homology domain interacting protein) directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. Our demonstration that PHIP is involved in human energy homeostasis through transcriptional regulation of central melanocortin signaling has potential diagnostic and therapeutic implications for patients with obesity and developmental delay. Additionally, we found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies. Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN., Methods: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants., Results: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) ( P =3.29×10 -8 ; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 ( P =1.21×10 -8 ; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure., Conclusions: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases., (Copyright © 2020 by the American Society of Nephrology.)

Background: Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors, but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxiety and broad assessment of risks to facilitate future research., Methods: The Genetic Links to Anxiety and Depression (GLAD) Study (www.gladstudy.org.uk) recruits individuals with depression or anxiety into the NIHR Mental Health BioResource. Participants invited to join the study (via media campaigns) provide demographic, environmental and genetic data, and consent for medical record linkage and recontact., Results: Online recruitment was effective; 42,531 participants consented and 27,776 completed the questionnaire by end of July 2019. Participants' questionnaire data identified very high rates of recurrent depression, severe anxiety, and comorbidity. Participants reported high rates of treatment receipt. The age profile of the sample is biased toward young adults, with higher recruitment of females and the more educated, especially at younger ages., Discussion: This paper describes the study methodology and descriptive data for GLAD, which represents a large, recontactable resource that will enable future research into risks, outcomes, and treatment for anxiety and depression., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Goal-classification of person-centred goals, using Goal Attainment Scaling for leg spasticity treatment. Methods: The study was conducted in two phases: phase I, a retrospective review to evaluate categories of goal set in routine clinical practice. Findings were used to design a goal classification system. Phase II, a multi-centre study to confirm the goal categories. Goals set ( n  = 270) were analysed from data collected at three centres in the UK (one centre for phase I). Goal categories were mapped onto the domains of the World Health Organisation, International Classification of Functioning Disability and Health. Results: One hundred and twenty seven participants were recruited in two cohorts: phase I: 63; phase II: 64. Goal categories using both cohorts were assigned to two domains, each subdivided into three key goal categories: Domain 1 : body structure impairment 121 (44%): (a) pain/discomfort 34 (12%), (b) involuntary movements 20 (7%), and (c) range of movement/contracture prevention 67 (25%). Domain 2 : activity function 149 (56%): (a) passive function (ease of caring for the affected limb) n  = 89 (33%), (b) active function (transfers) 26 (10%), and (c) active function (mobility) 27 (10%), other n  = 7 (3%). Conclusions: Patients individual leg spasticity goals can be grouped into six categories and two domains, which will assist clinicians, patients and cares in setting and evaluating goals in practice. Implications for Rehabilitation Six goal areas used in clinical goal setting for leg spasticity management were identified, under the two domains: (1) body structure impairment: pain, involuntary movements, and range of movement and (2) activities/function: passive function (ease of caring), active function - transfers or standing and active function - mobility. Categorisation of goals is consistent on repeated evaluation and across different clinical services. Using clinical goals for leg spasticity treatment is an effective method to identify treatment priorities.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: African-born individuals in the U.S. are disproportionately affected by HIV yet have low HIV testing rates. We conducted a mixed methods study to assess the uptake and feasibility of a novel strategy for integrating HIV testing into residential health fairs among African-born individuals in Seattle, WA., Methods: From April to May 2018, we held six health fairs at three apartment complexes with high numbers of African-born residents. Fairs included free point-of-care screening for glucose, cholesterol, body mass index, blood pressure, and HIV, as well as social services and health education. The health fairs were hosted in apartment complex common areas with HIV testing conducted in private rooms. Health fair participants completed a series of questionnaires to evaluate demographics, access to health services, and HIV testing history. We conducted 18 key informant interviews (KIIs) with health fair participants and community leaders to identify barriers to HIV testing among African-born individuals., Results: Of the 111 adults who accessed at least one service at a health fair, 92 completed questionnaires. Fifty-five (61%) were female, 48 (52%) were born in Africa, and 55 (63%) had health insurance. Half of African-born participants accepted HIV testing; all tested negative. The most common reasons for declining testing were lack of perceived risk for HIV and knowledge of HIV status. We identified a high prevalence of non-communicable diseases (NCDs) among health fair participants; among those tested, 77% (55/71) were overweight/obese, 39% (31/79) had blood pressure > 140/90 mmHg, and 30% (22/73) had total cholesterol > 200 mg/dL. KIIs identified community stigma and misinformation as major barriers to HIV testing among African-born individuals., Conclusions: Residential health fairs are a feasible method to increase HIV testing among African-born individuals in Seattle. The high prevalence of NCDs highlights the importance of integrating general preventive services within HIV testing programs in this population., Competing Interests: The authors have declared that no competing interests exist.

Objective: To identify barriers to appropriate referral and treatment for patients with spasticity and present solutions that address these in a pragmatic way., Methods: Using the findings of interviews conducted with UK healthcare professionals on the management of post-stroke spasticity, a consensus meeting was held involving 7 UK spasticity experts. The panel identified barriers to timely identification and referral of patients in the acute and post-acute care settings. Barriers were prioritized using a consensus framework based on impact and resolvability and a series of final recommendations were agreed., Results: High-priority barriers broadly related to: insufficient awareness of spasticity symptoms and benefits of treatment, limited access to spasticity services and lack of standardized pathways for post-stroke spasticity identification. Potential solutions included the appointment of an experienced member of the acute team to gain expertise in spasticity identification, patient education of spasticity symptoms and a greater utilization of training resources for healthcare professionals., Conclusion: To address the barriers identified, we provide a series of consensus recommendations. As a key recommendation, we propose a set of indicators for the identification of stroke patients requiring specialist assessment and the use of the associated acronym "ACTION"., Competing Interests: Gerry Christofi has received educational grants from Allergan. Stephen Ashford has undertaken research sponsored by investigator-led grants from Ipsen Ltd and has received sponsorship from Allergan, Ipsen and Merz to attend conferences and meetings in the UK and overseas, and was the editor of the Royal College of Physicians report on adult spasticity. Jonathan Birns has no conflicts of interests to declare. Catherine Dalton received salary support from Elan (through a grant held by the Institute of Neurology) to analyse MRI data from 2000 to 2003. Lynsay Duke was part of the National Guidelines group involved with the second edition of the RCP Spasticity in Adults: Management Using Botulinum Toxin (2018). She has undertaken research sponsored by an investigator-led grant from Ipsen Ltd and has received sponsorship from Ipsen and Merz to attend conferences and meetings in the UK and overseas. Claire Madsen has received sponsorship from Allergan, Ipsen and Merz to attend conferences and meetings in the UK. Sohail Salam has received sponsorship from Ipsen and Merz to attend conferences and meetings in the UK and overseas. He has also attended advisory meetings for Ipsen and Merz., (Journal Compilation © 2018 Foundation of Rehabilitation Information.)

Spastic paresis is a common feature of an upper motor neuron impairment caused by stroke, brain injury, multiple sclerosis and other central nervous system (CNS) disorders. Existing national and international guidelines for the treatment of adult spastic paresis tend to focus on the treatment of muscle overactivity rather than the comprehensive approach to care, which may require life-long management. Person-centered care is increasingly adopted by healthcare systems in a shift of focus from "disease-oriented" towards "person-centered" medicine. The challenge is to apply this principle to the complex management of spastic paresis and to include an educative process that engages care providers and patients and encourages them to participate actively in the long-term management of their own disease. To address this issue, a group of 13 international clinicians and researchers used a pragmatic top-down methodology to evaluate the evidence and to formulate and grade the strength of recommendations for applying the principles of person-centered care to the management of spastic paresis. There is a distinct lack of clinical trial evidence regarding the application of person-centered medicine to the rehabilitation setting. However, the current evidence base supports the need to ensure that treatment interventions for spastic paresis should be centered on as far as reasonable on the patient's own priorities for treatment. Goal setting, negotiation and formal recording of agreed SMART goals should be an integral part of all spasticity management programs, and goal attainment scaling should be recorded alongside other standardized measures in the evaluation of outcome. When planning interventions for spastic paresis, the team should consider the patient and their family's capacity for self-rehabilitation, as well as ways to enhance this approach. Finally, the proposed intervention and treatment goals should consider the impact of any neuropsychological, cognitive and behavioral deficits on rehabilitation. These recommendations support a person-centric focus in the management of spastic paresis.

Background: Upper limb hemiplegia following cerebrovascular diseases can result in significant functional limitation. To assess such functional disturbance requires a comprehensive, valid and reliable tool. The Arm Activity Measure (ArmA) is a comprehensive, valid and reliable self-report questionnaire to assess real-life function for upper limb hemiplegia. However, it has never been translated for use in different languages. The purpose of this study is to translate and cross-culturally adapt the Arm Activity Measure (ArmA) questionnaire into a Thai version and to evaluate content validity, internal consistency and feasibility., Methods: The ArmA was translated and culturally adapted according to published cross-cultural adaptation guidelines resulting in the Thai version of ArmA (ArmA-TH). Forty Thai patients with upper limb hemiplegia resulting from cerebrovascular disorders participated in field-testing of the ArmA-TH. Its feasibility was evaluated. Content validity index for item (I-CVI) and score (S-CVI) were examined. Inter-rater reliability was evaluated by Gwet's AC2. Internal consistency was measured using Cronbach's alpha coefficient., Results: Forty patients (29 males, 11 females) with upper limb spasticity due to stroke or TBI were included. The average age of patients was 54.5 years (SD 15.0). Twenty-seven patients (67.5%) completed the questionnaire within 5 min or less, average time taken was 4.45 (1.73) min. For both subscales, patients reported the ArmA-TH to be relevant (85%) and easy to use (67.5%). More than 80% of patients found the passive subscale useful, almost 80% found the active subscale useful. Overall S-CVI was 0.83, S-CVI for passive and active function subscale was 0.79 and 0.86 respectively. The inter-rater reliability coefficients for ArmA-TH was 0.81. Cronbach's alpha was 0.90 for the overall ArmA, 0.89 and 0.88 for the passive and active function subscales., Conclusions: The ArmA-TH was a feasible self-report questionnaire to assess hemiplegic upper limb function with good content validity, inter-rater reliability and internal consistency.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ 2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: In rehabilitation studies, it is critical to understand the constituents of interventions. First, to enable replication of the work and second, to identify what treatments work best. The development of a tool to describe and quantify therapy interventions in the context of focal spasticity management is presented., Methods: Potential intervention categories were identified from: (a) retrospective analysis of prospectively collected data from a cohort of patients (n = 62) receiving physical interventions in the context of botulinum toxin (BoNT) injection for leg spasticity and (b) cognitive de-briefing with Patient and Carer Advisory Group (PCAG) of patient and carer dyads (n = 8). Item reduction was achieved through consultation with a purposively-selected group of physiotherapists and occupational therapists (n = 16) in a two-round Delphi process. This was followed by review of findings by PCAG members., Results: A list of 24 possible therapy categories were identified and then reduced, resulting in a tool with two domains: (1) postural management; four categories and (2) exercise and retraining; four categories. The Leg Therapy recording Schedule (LegTS) wording and presentation were refined for clinical and research use., Conclusions: The LegTS is designed to record therapy interventions for the paretic lower limb in the context of spasticity intervention. Content and face validity have initially been addressed within the development process. Implications for Rehabilitation Clinicians need to understand intervention effectiveness, and to do so, it is critical to capture all the components of a complex intervention. In clinical practice or research, patient experience measures are required to capture the complexity of intervention provided and monitor intervention effectiveness on a case by case basis. Clinicians involved in rehabilitation and management of focal spasticity in the leg can use the Leg Therapy recording Schedule (LegTS) to enable an understanding of the entirety of the intervention package provided.

Purpose: The Disabilities of Arm, Shoulder and Hand (DASH) questionnaire is a patient reported outcome measure for evaluating upper limb function in people with musculoskeletal conditions. While the DASH has good psychometric properties when used with people with musculoskeletal conditions, it has not been tested with adults after stroke., Methods: Data for n = 61 adults following stroke (aged 32-93 years, 44% male) were analyzed to test validity and reliability of the DASH for use with a stroke population. Data included demographic and clinical attributes, DASH scores (baseline and four weeks later) and Patient Rated Wrist Evaluation (PRWE) measures., Results: Internal consistency was good (Cronbach alpha 0.92, SEM 6.65). Factor analysis and Rasch modeling suggested that the questionnaire comprised three subscales: pain, impact and function. Concurrent validity between the DASH and PRWE (Spearman's Rho r s  =   0.41) was moderate. The scale was perceived by clinicians to be useful, quick and simple to administer. The DASH had low four-week test-retest reliability (ICC 0.56 [95% Cl 0.05-0.79])., Conclusions: The DASH is considered to have acceptable validity when used with adults following stroke. Test-retest reliability was low but further research is needed to establish whether this is a result of condition-related change or the stability of the measure. Implications for Rehabilitation The DASH questionnaire examines upper limb function in task performance and appears to be a useful tool, which is simple to administer in the clinical setting with adults following stroke. Upper limb function post stroke can be meaningfully assessed using the DASH as it has good internal consistency and moderate concurrent validity. Rasch analysis and factor analysis suggests that the tool appears to consist of three subscales: pain, impact and function. The total score of the DASH may be less meaningful than the totals of these subscales. The test-retest reliability of the DASH requires further research; over a four-week period DASH stability was poor in a group of people with moderate to severe upper limb impairment.

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions.

This corrects the article DOI: 10.1038/nature22403.

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10 -3 ), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Background and Purpose: The purpose of the paper is to develop a patient-reported outcome measure of active and passive function in the paretic lower limb with associated spasticity., Methods: Potential items for inclusion were identified through (1) systematic review and analysis of existing measures and (2) analysis of the primary goals for treatment in a spasticity service. Ethical approval for re-evaluation of routinely collected data was received. Item reduction was achieved through consultation with a purposively selected group of experienced physiotherapists and occupational therapists (n = 16) in a two-round Delphi process. This was followed by a review of Delphi consultation findings by the Project Advisory Group consisting of patients and carers., Results: Development of the leg activity measure (LegA) included two rounds of Delphi consultation, which resulted in a high degree of agreement (80% in round 2) between respondents in rounds 1 and 2. From an initial shortlist of 126 items, 29 items were initially identified for inclusion in LegA and subsequently refined to a 24-item (two sub-scales) tool consisting of nine passive function and 15 active function items., Discussion: The Delphi consultation with clinicians experienced in this area of practice ensured content validity and appropriate reduction of items. In common with previous work in the upper limb, a 5-point ordinal scaling structure was chosen, with ratings based on activity over the preceding 7 days. The LegA is designed to measure passive and active function following focal interventions associated with spasticity in the lower limb. Content and face validity have initially been addressed within the development process. The next phase of development will involve formal evaluation of psychometric properties. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14 + monocytes, CD16 + neutrophils, and naive CD4 + T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Describe the rationale and protocol for the Upper Limb International Spasticity (ULIS)-III study, which aims to evaluate the impact of integrated spasticity management, involving multiple botulinum toxin A (BoNT-A) injection cycles and concomitant therapies, on patient-centred goal attainment. Outline novel outcome assessment methods for ULIS-III and report initial evaluation data from goal setting in early stages of the study., Design: Large international longitudinal cohort study of integrated upper limb spasticity management, including BoNT-A., Participants and Setting: ULIS-III is a 2-year study expected to enrol >1000 participants at 58 study centres across 14 countries., Interventions: The study design is non-interventional and intended to reflect real-life clinical practice. It will describe injection practices and additional treatment strategies, and record clinical decision-making in a serial approach to long-term spasticity management., Outcome Measures: ULIS-III will use a goal-directed approach to selection of targeted standardised measures to capture the diversity of presentation, goals and outcomes. ULIS-III will implement the Upper Limb Spasticity Index, a battery of assessments including a structured approach to goal attainment scaling (Goal Attainment Scaling-Evaluation of Outcomes for Upper Limb Spasticity tool), alongside a limited set of standardised measures, chosen according to patients' selected goal areas. Concomitant therapy inputs, patient satisfaction with engagement in goal setting, health economic end points and health-related quality of life data will also be captured., Results of Initial Evaluation of Goal Quality: Recruitment started in January 2015. By June 2015, 58 sites had been identified and initial data collected for 79 patients across 13 sites in 3 countries. Goal setting data were quality-checked and centres rated on the basis of function-related and Specific, Measurable, Achievable, Realistic, Timed (SMART) characteristics of goal statements. Overall, 11/13 centres achieved the highest rating (A++)., Conclusions: ULIS-III will provide valuable information regarding treatment of and outcomes from real-life upper limb spasticity management worldwide., Trial Registration Number: NCT02454803; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity., (© 2016 by The American Society of Hematology.)

Objective: We aimed to develop a goal classification of individualised goals for spasticity treatment incorporating botulinum toxin intervention for upper limb spasticity to under-pin a more structured approach to future goal setting., Design: Individualised goals for spasticity treatment incorporating botulinum toxin intervention for upper limb spasticity (n=696) were analysed initially from four studies published in 2008-2012, spanning a total of 18 centres (12 in the UK and 6 in Australia). Goals were categorised and mapped onto the closest matching domains of the WHO International Classification of Functioning. Confirmatory analysis included a further 927 goals from a large international cohort study spanning 22 countries published in 2013., Results: Goal categories could be assigned into two domains, each subdivided into three key goal areas: Domain 1: symptoms/impairment n=322 (46%): a. pain/discomfort n=78 (11%), b. involuntary movements n=75 (11%), c. range of movement/contracture prevention n=162 (23%). Domain 2: Activities/function n=374 (54%): a. passive function (ease of caring for the affected limb) n=242 (35%), b active function (using the affected limb in active tasks) n=84 (12%), c. mobility n=11 (2%).Over 99% of the goals from the large international cohort fell into the same six areas, confirming the international applicability of the classification., Conclusions: Goals for management of upper limb spasticity, in worldwide clinical practice, fall into six main goal areas., (© The Author(s) 2015.)

The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patients with myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of α-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC-positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets and MKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors., (Copyright © 2016, American Association for the Advancement of Science.)

Purpose: To evaluate the conformity of the Arm Activity measure (ArmA) passive function sub-scale to the Rasch model., Methods: A consecutive cohort of patients (n = 92) undergoing rehabilitation, including upper limb rehabilitation and spasticity management, at two specialist rehabilitation units were included. Rasch analysis was used to examine scaling and conformity to the model. Responses were analysed using Rasch unidimensional measurement models (RUMM 2030). The following aspects were considered: overall model and individual item fit statistics and fit residuals, internal reliability, item response threshold ordering, item bias, local dependency and unidimensionality., Results: ArmA contains both active and passive function sub-scales, but in this analysis only the passive function sub-scale was considered. Four of the seven items in the ArmA passive function sub-scale initially had disordered thresholds. These items were rescored to four response options, which resulted in ordered thresholds for all items. Once the items with disordered thresholds had been rescored, item bias was not identified for age, global disability level or diagnosis, but with a small difference in difficulty between males and females for one item of the scale. Local dependency was not observed and the unidimensionality of the sub-scale was supported and good fit to the Rasch model was identified. The person separation index (PSI) was 0.95 indicating that the scale is able to reliably differentiate at least two groups of patients., Conclusions: The ArmA passive function sub-scale was shown in this evaluation to conform to the Rasch model once disordered thresholds had been addressed. Using the logit scores produced by the Rasch model it was possible to convert this back to the original scale range. Implications for Rehabilitation The ArmA passive function sub-scale was shown, in this evaluation, to conform to the Rasch model once disordered thresholds had been addressed and therefore to be a clinically applicable and potentially useful hierarchical measure. Using Rasch logit scores it has be possible to convert back to the original ordinal scale range and provide an indication of real change to enable evaluation of clinical outcome of importance to patients and clinicians.

Background: Spasticity in the upper limb is common after acquired brain impairment and may have a significant impact on the ability to perform meaningful daily activities. Traditionally, outcome measurement in spasticity rehabilitation has focused on impairment, however, improvements in impairments do not necessarily translate to improvements in an individual's ability to perform activities or engage in life roles. There is an increasing need for outcome measures that capture change in activity performance and life participation., Methods/design: We will conduct a systematic review of the psychometric properties of instruments used to measure upper limb functional outcomes (activity performance and participation) in patients with spasticity. Assessments (n = 27) will be identified from a recently published systematic review of assessments that measure upper limb function in neurological rehabilitation for adults with focal spasticity, and a systematic review of each assessment will then be conducted. The databases MEDLINE, CINAHL and EMBASE will be searched from inception. Search strategies will include the name of the assessment and the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) published search strategy for identifying studies of measurement properties. The methodological rigour of the testing of the psychometric quality of instruments will be undertaken using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist. International Classification of Functioning, Disability and Health (ICF) definitions of impairment, activity and participation will be used for content analysis of items to determine the extent to which assessments are valid measures of activity performance and life participation. We will present a narrative synthesis on the psychometric properties and utility of all instruments and make recommendations for assessment selection in practice., Discussion: This systematic review will present a narrative synthesis on the psychometric properties and utility of assessments used to evaluate function in adults with upper limb focal spasticity. Recommendations for assessment selection in practice will be made which will aid clinicians, managers and funding bodies to select an instrument fit for purpose. Importantly, appropriate assessment selection will provide a mechanism for capturing how applicable to everyday life the outcomes from individualised rehabilitation programs for the upper limb really are., Systematic Review Registration: PROSPERO CRD42014013190.

In this post-hoc analysis of the ULIS-II study, we investigated factors influencing person-centred goal setting and achievement following botulinum toxin-A (BoNT-A) treatment in 456 adults with post-stroke upper limb spasticity (ULS). Patients with primary goals categorised as passive function had greater motor impairment (p < 0.001), contractures (soft tissue shortening [STS]) (p = 0.006) and spasticity (p = 0.02) than those setting other goal types. Patients with goals categorised as active function had less motor impairment (0.0001), contracture (p < 0.0001), spasticity (p < 0.001) and shorter time since stroke (p = 0.001). Patients setting goals for pain were older (p = 0.01) with more contractures (p = 0.008). The proportion of patients achieving their primary goal was not impacted by timing of first-ever BoNT-A injection (medium-term (≤1 year) vs. longer-term (>1 year)) post-stroke (80.0% vs. 79.2%) or presence or absence of severe contractures (76.7% vs. 80.6%), although goal types differed. Earlier BoNT-A intervention was associated with greater achievement of active function goals. Severe contractures impacted negatively on goal achievement except in pain and passive function. Goal setting by patients with ULS is influenced by impairment severity, age and time since stroke. Our findings resonate with clinical experience and may assist patients and clinicians in selecting realistic, achievable goals for treatment.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease for which there is no cure. We have previously developed a Drosophila model of ALS based on TDP-43 that recapitulates several aspects of disease pathophysiology. Using this model, we designed a drug screening strategy based on the pupal lethality phenotype induced by TDP-43 when expressed in motor neurons. In screening 1200 FDA-approved compounds, we identified the PPARγ agonist pioglitazone as neuroprotective in Drosophila. Here, we show that pioglitazone can rescue TDP-43-dependent locomotor dysfunction in motor neurons and glia but not in muscles. Testing additional models of ALS, we find that pioglitazone is also neuroprotective when FUS, but not SOD1, is expressed in motor neurons. Interestingly, survival analyses of TDP or FUS models show no increase in lifespan, which is consistent with recent clinical trials. Using a pharmacogenetic approach, we show that the predicted Drosophila PPARγ homologs, E75 and E78, are in vivo targets of pioglitazone. Finally, using a global metabolomic approach, we identify a set of metabolites that pioglitazone can restore in the context of TDP-43 expression in motor neurons. Taken together, our data provide evidence that modulating PPARγ activity, although not effective at improving lifespan, provides a molecular target for mitigating locomotor dysfunction in TDP-43 and FUS but not SOD1 models of ALS in Drosophila. Furthermore, our data also identify several 'biomarkers' of the disease that may be useful in developing therapeutics and in future clinical trials., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)