Reablement services for people at risk of needing social care: the MoRe mixed-methods evaluation.

Background Reablement is an intensive, time-limited intervention for people at risk of needing social care or increased intensity of care. Differing from homecare, it seeks to restore functioning and self-care skills. In England, it as a core element of intermediate care. The existing evidence base is limited. Aims Describe reablement services in England and develop a service model typology; Conduct a mixed method comparative evaluation of service models investigating outcomes, factors impacting outcomes, costs and cost-effectiveness, and user and practitioner experiences; Investigate specialist reablement services/practices for people with dementia. Methods Work package 1 (WP1), taking place in 2015, surveyed reablement services in England. Data were collected on organisational characteristics, service delivery and practice, and service costs and caseload. Work package 2 (WP2) was an observational study of three reablement services, each representing a different service model. Data collected included: health- (EQ-5D-5L) and social care-related (ASCOT SCT-4) quality of life, practitioner (Barthel Index) and self-reported (NEADL scale) functioning, individual and service characteristics, and resource use. It was collected on entry into reablement (n=186), at discharge (n=128) and, for those reaching the timepoint within the study timeline, six months post-discharge (n=64). Interviews with staff and service users explored experiences of delivering or receiving reablement and its perceived impacts. Work package 3 (WP3) interviewed staff in eight reablement services to investigate experiences of reabling people with dementia. Results 201 services, located in 139 Local Authorities took part in the survey. Services varied in their organisational base, relationship with other intermediate care services, use of out-sourced providers, skill mix, and scope of reablement input. These characteristics influenced aspects of service delivery and practice. Average cost per case was £1,728. Lower than expected sample sizes meant a comparison of service models in WP2 was not possible. Findings are preliminary. At T1, significant improvements in mean score on outcome measures except self-reported functioning were observed. Further improvements were observed at T2, but only significant for self-reported functioning. There was some evidence that individual (e.g. engagement, mental health) and service (e.g. service structure) characteristics were associated with T1 outcomes and resource use. Staff views on factors affecting outcomes typically aligned with, or offered possible explanations for, these associations. However, it was not possible to establish the significance of these findings in terms of practice or commissioning decisions. Service users expressed satisfaction with reablement and identified two core impacts: regained independence and, during reablement, companionship. Staff participating in WP3 believed people with dementia can benefit from reablement, but objectives may differ and expectations for regained independence inappropriate. Furthermore, practice (e.g. duration of home visits) should be adjusted and staff adequately trained. Conclusions The study contributes to our understanding of reablement, and what impacts on outcomes and costs. Staff believe reablement can be appropriate for people with dementia. Findings will be of interest to commissioners and service managers. Future research should further investigate factors impacting on outcomes, and reabling people with dementia

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Adherence to the type 1 diabetes treatment regime in adolescents and young adults

Non-adherence to the type 1 diabetes treatment regime is an ongoing problem that is costly on both an individual and societal level. Adolescents and young adults have some of the lowest rates of adherence to the regime. The first paper is a systematic review of 27 quantitative studies investigating the influence of the family on adolescent adherence. Key findings included the importance of a high-quality adolescent-parent relationship characterised by high-levels of cohesion, collaboration and support. Parental well-being and parenting style was also shown to influence adolescent adherence. The positive association of parental diabetes-specific monitoring with adolescent adherence was also highlighted. Clinical implications include the need for interventions that enhance the parent-adolescent relationship and that educate parents about helpful parenting styles and strategies for involvement in their adolescent's diabetes management. The second paper focused attention on one particular diabetes adherence behaviour about which little is understood; non-attendance at diabetic retinopathy screening appointments. The study aimed to understand the experiences of young people who repeatedly do not attend these appointments and identify the factors influencing their attendance decisions. A qualitative study which employed a modified grounded theory methodology was carried out. Semi-structured interviews were used to explore the experiences of nine young adults diagnosed with type 1 diabetes. The grounded theory model developed illustrates that participants both knew and believed they should attend screening. This created conflict with their actual non-attendance behaviour. Four strategies that participants employed to resolve this conflict were identified and were facilitated by a number of external and cognitive factors. One incentive to attend screening was identified and was participants' desire to obtain reassurance about the health status of their eyes. Interventions that reduce the perceived 'hassle' associated with attendance are recommended, as are interventions that encourage a realistic perception of the risk of developing diabetic retinopathy.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The Handbook of Phonetic Sciences

"With this second edition, the Handbook of Phonetics Sciences will continue to be an outstanding resource for students, providing wide-ranging critical overviews of the development of key scientific topics and of the debates which are at the heart of contemporary phonetic research." - Gerard Docherty, Newcastle University "This book is an outstanding collection of state-of-the-art surveys and original contributions. Revised and refreshed, it is essential reading for anyone engaged in understanding phonetic aspects of speech. " -John Local, University of York "This new edition updates its coverage of a wide range of topics, reflecting the most recent trends in research. I will use it as a reference for both my teaching and my research." -Patricia Keating, University of California, Los Angeles.Intro -- The Handbook of Phonetic Sciences -- Contents -- Contributors -- Preface to the Second Edition -- Introduction -- Part I Experimental Phonetics -- 1 Laboratory Techniques for Investigating Speech Articulation -- 1 Imaging Techniques -- 1.1 X-ray -- 1.2 Tomography -- 2 Point-Tracking Measurements of the Vocal Tract -- 2.1 Electromagnetic Articulometer (EMA) -- 2.2 X-ray Microbeam -- 2.3 Optotrak -- 3 Measurement of Tongue-Palate Interaction -- 3.1 Tongue-palate contact -- 3.2 Tongue-palate pressure -- 2 The Aerodynamics of Speech -- 1 Introduction -- 2 Basic Considerations -- 3 Aerodynamically Distinct Tract Behaviors -- 3.1 Breathing -- 3.2 Frication -- 3.3 Transient excitation: Stops -- 3.4 Mechanical oscillation: Trills and voicing -- 3.5 Aerodynamic oscillation: Whistling -- 4 Measurement Methods -- 4.1 Basic methods -- 4.2 Speech-adapted methods -- 5 Models Incorporating Aerodynamics -- 3 Acoustic Phonetics -- 1 Introduction -- 2 Vowels, Vowel-Like Sounds, and Formants -- 2.1 The F1 × F2 plane -- 2.2 F3 and f0 -- 2.3 Dynamic cues to vowels -- 2.4 Whole-spectrum approaches to vowel identification -- 2.5 Vowel reduction -- 2.6 F2 locus and consonant place of articulation -- 2.7 Approximants -- 3 Obstruents -- 3.1 Place of articulation: Spectral shape -- 3.2 Place of articulation in obstruents: Other cues -- 3.3 Obstruent voicing -- 4 Nasal Consonants and Nasalized Vowels -- 5 Concluding Comment -- 4 Investigating the Physiology of Laryngeal Structures -- 1 Introduction: Basic Laryngeal Functions -- 2 Methods of Investigating Laryngeal Function in Speech -- 2.1 Fiberoptic observation and measurement of vocal fold movement -- 2.2 High-speed digital imaging of vocal fold vibration -- 2.3 Laryngeal electromyography -- 2.4 Photoglottography (transillumination of the glottis) -- 2.5 Electroglottography (laryngography)2.6 New imaging techniques including Magnetic Resonance Imaging (MRI) -- 3 Laryngeal Structures and the Control of Phonation -- 3.1 Laryngeal framework and laryngeal muscles -- 3.2 Layered structure of the vocal fold -- 3.3 Vocal fold vibration during phonation -- 4 Laryngeal Adjustments for Different Phonetic Conditions -- 4.1 Abduction vs. adduction of the vocal folds -- 4.2 Constriction of the supraglottal structures -- 4.3 Adjustment of the length, stiffness, and thickness of the vocal folds with respect to pitch control -- 4.4 Elevation and lowering of the entire larynx -- 5 Current Main Issues and the Direction of Future Research -- Part II Biological Perspectives -- 5 Organic Variation of the Vocal Apparatus -- 1 Introduction -- 1.1 The relevance of organic variation forphonetic science -- 1.2 Sources of individual variation -- 2 Life-Cycle Changes in the Vocal Apparatus -- 2.1 The respiratory system: The lungs and thorax -- 2.2 The phonatory system: The larynx -- 2.3 Resonating cavities: Pharynx, oral cavity, and nasal cavity -- 2.4 Summary of vocal apparatus changes occurring during the three phases of life -- 2.5 Consequences of growth and change for speech production -- 3 Interpersonal Variation -- 3.1 Sources of interpersonal variation -- 3.2 Illustrations of organic variations with phonetic relevance -- 4 Variation Resulting from Trauma or Disease -- 4.1 Illustrative examples of the phonetic consequences of disease or trauma -- 5 Conclusion -- 6 Brain Mechanisms Underlying Speech Motor Control -- 1 Introduction -- 2 Macroand Microstructural Characteristics of the Brain in Subhuman Primates and Man -- 3 Acoustic Communication in Monkeys and Apes -- 4 Cerebral Representation of Orofacial and Laryngeal Musculature in Subhuman Primates -- 4.1 Compartmentalization of primary and nonprimary motor cortex4.2 Organization of corticobulbar tracts and cranial nerve nuclei -- 5 Morphological Asymmetries of Primary and Nonprimary Motor Areas in Subhuman Primates and Man -- 6 Cortical Maps of Vocal Tract Muscle Representation in Humans -- 7 Electroand Magnetoencephalographic Measurements of the Time Course of Brain Activity Related to Spreech Production -- 8 Clinical Data: Compromised Motor Aspects of Speech Production in Focal Brain Lesions and Degenerative Diseases of the Central -- 8.1 Dissociations of verbal and nonverbal vocal tract motor functions -- 8.2 Compromised motivational mechanisms of verbal communication: The role of mesiofrontal cortex -- 8.3 Impaired phonetic planning mechanisms in language production: The role of left-hemisphere inferior dorsolateral frontal and -- 8.4 Impaired motor execution mechanisms engaged in speech production -- 9 Cerebral Networks of Speech Motor Control: Functional Hemodynamic Imaging Studies -- 9.1 Physiological background of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) -- 9.2 Cerebral correlates of the phonetic/articulatory stage of speech production -- 9.3 Functional organization of the cerebral network of speech motor control: Some insights from functional imaging -- 9.4 Covert generation of verbal utterances ("inner speech") -- 9.5 Comparison of verbal and nonverbal orofacial movements -- 9.6 Summary -- 10 Conclusions -- 10.1 Cerebral network of speech motor control -- 10.2 Speech production and vocal expression of emotions (affective vocalizations and affective prosody) -- 7 Development of Neural Control of Orofacial Movements for Speech -- 1 Introduction -- 2 Components of Articulatory Motor Control -- 2.1 Central mechanisms for articulatory control -- 2.2 Peripheral mechanisms in articulatory control and coordination -- 3 Development of Speech Motor Processes3.1 The emergence of early vocalizations and their relationship to pre-existing behaviors -- 3.2 Speech motor development in children -- 3.3 Theoretical issues and models of speech motor development -- Part III Modeling Speech Production and Perception -- 8 Speech Acquisition -- 1 The Problem -- 2 The Broader Context -- 3 Contemporary Theoretical Perspectives on Speech Acquisition -- 3.1 Formalist phonological perspectives -- 3.2 Functionalist phonetic perspectives -- 3.3 Auditory input perspectives -- 3.4 Cognitive science perspectives -- 4 Summary -- 9 Coarticulation and Connected Speech Processes -- 1 Speech Contextual Variability -- 1.1 Coarticulation -- 1.2 Assimilation -- 1.3 Connected speech processes -- 2 Theoretical Accounts of Coarticulation -- 2.1 Pioneering studies: Joos' overlapping innervation theory -- 2.2 Coarticulation as a component of the Grammar -- 2.3 Coarticulation as speech economy -- 2.4 The window model of coarticulation -- 2.5 Coarticulation as coproduction -- 2.6 Connected speech processes -- 3 Summary -- 10 Theories and Models of Speech Production -- 1 The Speech Signal and Its Description -- 2 Concepts and Issues in Movement Control -- 2.1 What happens when speech movements are perturbed? -- 2.2 Planning and execution of movements -- 2.3 Distributed control -- 2.4 Coordinate spaces -- 2.5 Coordinative structures -- 2.6 A gestural approach to speech production -- 2.7 Internal models -- 3 Serial Control of Speech Movements -- 4 Summary -- 11 Voice Source Variation and Its Communicative Functions -- 1 Introduction -- 2 Analyzing the Voice Source -- 2.1 Obtaining glottal flow: Inverse filtering -- 2.2 Voice source models -- 2.3 Measuring the glottal signal: Source model matching -- 2.4 Some important voice source parameters -- 2.5 Spectral measurements relevant to the voice source -- 3 Some Commonly Occurring Voice Qualities4 Determinants of Voice Source Variation -- 4.1 Linguistically determined variation of the source -- 4.2 Paralinguistic aspects of voice source variation -- 4.3 Sociolinguistic and cross-language variation -- 4.4 Extralinguistic determinants of the voice source -- 5 Future Research -- 12 Articulatory朅coustic Relations as the Basis of Distinctive Contrasts -- 1 The Question: How Is the Discrete LinguisticRepresentation of an Utterance Related to theContinuously-Varying Speech Signal? -- 2 One Answer: Quantal Theory and Distinctive Features -- 2.1 Where quantal relations come from -- 3 Enhancement and Overlap: Introducing Variation to the Defining Acoustic Cues -- 4 Concluding Remarks -- 4.1 Other models of speech processing -- 4.2 Problems for future research -- 13 Aspects of Auditory Processing Related to Speech Perception -- 2 Frequency Selectivity -- 2.1 The concept of the auditory fi lter -- 2.2 Psychophysical tuning curves -- 2.3 The notched-noise method -- 2.4 Masking patterns and excitation patterns -- 2.5 Excitation pattern of a vowel sound -- 3 Across-Channel Processes in Masking -- 3.1 Co-modulation masking release -- 3.2 Profile analysis -- 4 Timbre Perception -- 4.1 Role of spectral shape for steady sounds -- 4.2 Other factors affecting timbre -- 4.3 Perceptual compensation for spectral distortion -- 5 The Perception of Pitch -- 5.1 The phenomenon of the missing fundamental -- 5.2 The principle of dominance -- 5.3 Discrimination of the pitch of complex tones -- 5.4 Perception of pitch in speech -- 6 Temporal Analysis -- 6.1 Within-channel temporal analysis using broadband sounds -- 6.2 Within-channel temporal analysis using narrowband sounds -- 6.3 Modeling temporal resolution -- 7 Calculation of the Internal Representation of Sounds -- 14 Cognitive Processes in Speech Perception -- 1 Introduction -- 2 Lexical Information2.1 Lexical effects"With this second edition, the Handbook of Phonetics Sciences will continue to be an outstanding resource for students, providing wide-ranging critical overviews of the development of key scientific topics and of the debates which are at the heart of contemporary phonetic research." - Gerard Docherty, Newcastle University "This book is an outstanding collection of state-of-the-art surveys and original contributions. Revised and refreshed, it is essential reading for anyone engaged in understanding phonetic aspects of speech. " -John Local, University of York "This new edition updates its coverage of a wide range of topics, reflecting the most recent trends in research. I will use it as a reference for both my teaching and my research." -Patricia Keating, University of California, Los Angeles.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries

Understanding and supporting user engagement in reablement

Main issue analysed and its relevance Existing evidence indicates that a number of person-centred factors reablement outcomes. These include service user understanding and expectations of the intervention, motivation, and acceptance of the need for help. Some person-centred factors are, potentially, amenable to change by the practitioners involved. Thus, aspects of service design and delivery are also implicated. In addition, and contributed to by both service user and practitioner, is the quality of the so-called ‘therapeutic alliance’. All these factors are components of the construct ‘intervention engagement’. However, despite reablement requiring active participation by the service user, the construct of engagement has not been investigated within this context. This paper reports findings from a study which begins to address this evidence gap. Methdology An observational study of individuals (n=186) receiving reablement in England, followed up for 6 months post-intervention. Four models of service delivery were represented. A measure of engagement, developed and evaluated by the research team, was included within a battery of measures. A nested qualitiative study investigated the views and experiences of service users, reablement staff, and senior practitioners. Together, these data have allowed us to: i) test and understand whether and how user engagement impacts on reablement outcomes; and ii) the ways that aspects of service design and delivery may moderate or mediate this association. Main findings expected from the analysis A first round of analysis of the quantitative data has found an association between user engagement and a range of outcome domains and that user engagement differed between service delivery models. Qualitative data offers some explanations for these findings. This paper will synthesise these findings and report further analyses looking at the involvement of mental health, and the association between engagement and longer-term outcomes. Finally, we will reflect on the study’s contribution to theory. We are interested in the fact that much writing on engagement is concerned with the relationship between user and worker yet, in reablement, multiple workers may be involved

FKBP12.6 activates RyR1 : investigating the amino acid residues critical for channel modulation

Funding: British Heart FoundationWe have previously shown that FKBP12 associates with RyR2 in cardiac muscle and that it modulates RyR2 function differently to FKBP12.6. We now investigate how these proteins affect the single-channel behavior of RyR1 derived from rabbit skeletal muscle. Our results show that FKBP12.6 activates and FKBP12 inhibits RyR1. It is likely that both proteins compete for the same binding sites on RyR1 because channels that are preactivated by FKBP12.6 cannot be subsequently inhibited by FKBP12. We produced a mutant FKBP12 molecule (FKBP12(E31Q/D32N/W59F)) where the residues Glu(31), Asp(32), and Trp(59) were converted to the corresponding residues in FKBP12.6. With respect to the functional regulation of RyR1 and RyR2, the FKBP12(E31Q/D32N/W59F) mutant lost all ability to behave like FKBP12 and instead behaved like FKBP12.6. FKBP12(E31Q/D32N/W59F) activated RyR1 but was not capable of activating RyR2. In conclusion, FKBP12.6 activates RyR1, whereas FKBP12 activates RyR2 and this selective activator phenotype is determined within the amino acid residues Glu31, Asp(32), and Trp(59) in FKBP12 and Gln(31), Asn(32), and Phe(59) in FKBP12.6. The opposing but different effects of FKBP12 and FKBP12.6 on RyR1 and RyR2 channel gating provide scope for diversity of regulation in different tissues.Publisher PDFPeer reviewe