Self-management Programs Within Rehabilitation Yield Positive Health Outcomes at a Small Increased Cost Compared With Usual Care: A Systematic Review and Meta-analysis.

OBJECTIVE: To determine if self-management programs, supported by a health professional, in rehabilitation are cost effective. DATA SOURCES: Six databases were searched until December 2023. STUDY SELECTION: Randomized controlled trials with adults completing a supported self-management program while participating in rehabilitation or receiving health professional input in the hospital or community settings were included. Self-management programs were completed outside the structured, supervised therapy and health professional sessions. Included trials had a cost measure and an effectiveness outcome reported, such as health-related quality of life or function. Grading of Recommendations, Assessment, Development, and Evaluations was used to determine the certainty of evidence across trials included in each meta-analysis. Incremental cost-effectiveness ratios were calculated based on the mean difference from the meta-analyses of contributing health care costs and quality of life. DATA EXTRACTION: After application of the search strategy, two independent reviewers determined eligibility of identified literature, initially by reviewing the title and/or abstract before full-text review. Using a customized form, data were extracted by one reviewer and checked by a second reviewer. DATA SYNTHESIS: Forty-three trials were included, and 27 had data included in meta-analyses. Where self-management was a primary intervention, there was moderate certainty of a meaningful positive difference in quality-of-life utility index of 0.03 units (95% confidence interval, 0.01-0.06). The cost difference between self-management as the primary intervention and usual care (comprising usual intervention/therapy, minimal intervention [including education only], or no intervention) potentially favored the comparison group (mean difference=Australian dollar [AUD]90; 95% confidence interval, -AUD130 to AUD310). The cost per quality-adjusted life year (QALY) gained for self-management programs as a stand-alone intervention was AUD3000, which was below the acceptable willingness-to-pay threshold in Australia per QALY gained (AUD50,000/QALY gained). CONCLUSIONS: Self-management as an intervention is low cost and could improve health-related quality of life.

Barriers and facilitators to implementing self-directed therapy activities in inpatient rehabilitation settings.

BACKGROUND: Self-directed therapy activities are not currently part of routine care during inpatient rehabilitation. Understanding patient and clinician perspectives on self-directed therapy is key to increasing implementation. The aim of this study was to investigate barriers and facilitators to implementing a self-directed therapy programme ("My Therapy") in adult inpatient rehabilitation settings. METHODS: My Therapy was recommended by physiotherapists and occupational therapists and completed by rehabilitation inpatients independently, outside of supervised therapy sessions. Physiotherapists, occupational therapists, and patients were invited to complete an online questionnaire comprising open-ended questions on barriers and facilitators to prescribing and participating in My Therapy. A directed content analysis of free-text responses was undertaken, with data coded using categories of the Capability, Opportunity, and Motivation Model of Behaviour (COM-B model). RESULTS: Eleven patients and 20 clinicians completed the questionnaire. Patient capability was reported to be facilitated by comprehensive education by clinicians, with mixed attitudes towards the format of the programme booklet. Clinician capability was facilitated by staff collaboration. One benefit was the better use of downtime between the supervised therapy sessions, but opportunities for patients to engage in self-directed therapy were compromised by the lack of space to complete the programme. Clinician opportunity was reported to be provided via organisational support but workload was a reported barrier. Patient motivation to engage in self-directed therapy was reported to be fostered by feeling empowered, engaged, and encouraged to participate. Clinician motivation was associated with belief in the value of the programme. CONCLUSION: Despite some barriers to rehabilitation patients independently practicing therapeutic exercises and activities outside of supervised sessions, both clinicians and patients agreed it should be considered as routine practice. To do this, patient time, ward space, and staff collaboration are required. Further research is needed to scale-up the implementation of the My Therapy programme and evaluate its effectiveness.

Self-managed occupational therapy and physiotherapy for adults receiving inpatient rehabilitation ('My Therapy'): protocol for a mixed-methods process evaluation.

BACKGROUND: Process evaluations have been recommended alongside clinical and economic evaluations to enable an in-depth understanding of factors impacting results. My Therapy is a self-management program designed to augment usual care inpatient rehabilitation through the provision of additional occupational therapy and physiotherapy exercises and activities, for the patient to complete outside of supervised therapy. The aims of the process evaluation are to assess the implementation process by investigating fidelity, quality of implementation, acceptability, adoption, appropriateness, feasibility and adaptation of the My Therapy intervention; and identify contextual factors associated with variations in outcomes, including the perspectives and experiences of patients and therapists. METHODS: The process evaluation will be conducted alongside the clinical and economic evaluation of My Therapy, within eight rehabilitation wards across two public and two private Australian health networks. All participants of the stepped wedge cluster randomised trial (2,160 rehabilitation patients) will be included in the process evaluation (e.g., ward audit); with a subset of 120 participants undergoing more intensive evaluation (e.g., surveys and activity logs). In addition, 24 staff (occupational therapists and physiotherapists) from participating wards will participate in the process evaluation. The mixed-methods study design will adopt a range of quantitative and qualitative research approaches. Data will be collected via a service profile survey and audits of clinical practice across the participating wards (considering areas such as staffing profiles and prescription of self-management programs). The intensive patient participant data collection will involve structured therapy participation and self-management program audits, Exercise Self Efficacy Scale, patient activity logs, patient surveys, and patient-worn activity monitors. Staff data collection will include surveys and focus groups. DISCUSSION: The process evaluation will provide context to the clinical and economic outcomes associated with the My Therapy clinical trial. It considers how clinical and economic outcomes were achieved, and how to sustain the outcomes within the participating health networks. It will also provide context to inform future scaling of My Therapy to other health networks, and influence future models of rehabilitation and related policy. TRIAL REGISTRATION: This study was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12621000313831; registered 22/03/2021, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380828&isReview=true ).

Self-managed occupational therapy and physiotherapy for adults receiving inpatient rehabilitation ('My Therapy'): protocol for a stepped-wedge cluster randomised trial.

BACKGROUND: Ensuring patients receive an effective dose of therapeutic exercises and activities is a significant challenge for inpatient rehabilitation. My Therapy is a self-management program which encourages independent practice of occupational therapy and physiotherapy exercises and activities, outside of supervised therapy sessions. METHODS: This implementation trial aims to determine both the clinical effectiveness of My Therapy on the outcomes of function and health-related quality of life, and cost-effectiveness per minimal clinically important difference (MCID) in functional independence achieved and per quality adjusted life year (QALY) gained, compared to usual care. Using a stepped-wedge cluster randomised design, My Therapy will be implemented across eight rehabilitation wards (inpatient and home-based) within two public and two private Australian health networks, over 54-weeks. We will include 2,160 patients aged 18 + years receiving rehabilitation for any diagnosis. Each ward will transition from the usual care condition (control group receiving usual care) to the experimental condition (intervention group receiving My Therapy in addition to usual care) sequentially at six-week intervals. The primary clinical outcome is achievement of a MCID in the Functional Independence Measure (FIM™) at discharge. Secondary outcomes include improvement in quality of life (EQ-5D-5L) at discharge, length of stay, 30-day re-admissions, discharge accommodation, follow-up rehabilitation services and adverse events (falls). The economic outcomes are the cost-effectiveness per MCID in functional independence (FIM™) achieved and per QALY gained, for My Therapy compared to usual care, from a health-care sector perspective. Cost of implementation will also be reported. Clinical outcomes will be analysed via mixed-effects linear or logistic regression models, and economic outcomes will be analysed via incremental cost-effectiveness ratios. DISCUSSION: The My Therapy implementation trial will determine the effect of adding self-management within inpatient rehabilitation care. The results may influence health service models of rehabilitation including recommendations for systemic change to the inpatient rehabilitation model of care to include self-management. Findings have the potential to improve patient function and quality of life, and the ability to participate in self-management. Potential health service benefits include reduced hospital length of stay, improved access to rehabilitation and reduced health service costs. TRIAL REGISTRATION: This study was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12621000313831; registered 22/03/2021, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380828&isReview=true ).

Solution NMR analyses of the C-type carbohydrate recognition domain of DC-SIGNR protein reveal different binding modes for HIV-derived oligosaccharides and smaller glycan fragments.

The C-type lectin DC-SIGNR (dendritic cell-specific ICAM-3-grabbing non-integrin-related; also known as L-SIGN or CD299) is a promising drug target due to its ability to promote infection and/or within-host survival of several dangerous pathogens (e.g. HIV and severe acute respiratory syndrome coronavirus (SARS)) via interactions with their surface glycans. Crystallography has provided excellent insight into the mechanism by which DC-SIGNR interacts with small glycans, such as (GlcNAc)2Man3; however, direct observation of complexes with larger, physiological oligosaccharides, such as Man9GlcNAc2, remains elusive. We have utilized solution-state nuclear magnetic resonance spectroscopy to investigate DC-SIGNR binding and herein report the first backbone assignment of its active, calcium-bound carbohydrate recognition domain. Direct interactions with the small sugar fragments Man3, Man5, and (GlcNAc)2Man3 were investigated alongside Man9GlcNAc derived from recombinant gp120 (present on the HIV viral envelope), providing the first structural data for DC-SIGNR in complex with a virus-associated ligand, and unique binding modes were observed for each glycan. In particular, our data show that DC-SIGNR has a different binding mode for glycans on the HIV viral envelope compared with the smaller glycans previously observed in the crystalline state. This suggests that using the binding mode of Man9GlcNAc, instead of those of small glycans, may provide a platform for the design of DC-SIGNR inhibitors selective for high mannose glycans (like those on HIV). (15)N relaxation measurements provided the first information on the dynamics of the carbohydrate recognition domain, demonstrating that it is a highly flexible domain that undergoes ligand-induced conformational and dynamic changes that may explain the ability of DC-SIGNR to accommodate a range of glycans on viral surfaces.

A redox 2-Cys mechanism regulates the catalytic activity of divergent cyclophilins.

The citrus (Citrus sinensis) cyclophilin CsCyp is a target of the Xanthomonas citri transcription activator-like effector PthA, required to elicit cankers on citrus. CsCyp binds the citrus thioredoxin CsTdx and the carboxyl-terminal domain of RNA polymerase II and is a divergent cyclophilin that carries the additional loop KSGKPLH, invariable cysteine (Cys) residues Cys-40 and Cys-168, and the conserved glutamate (Glu) Glu-83. Despite the suggested roles in ATP and metal binding, the functions of these unique structural elements remain unknown. Here, we show that the conserved Cys residues form a disulfide bond that inactivates the enzyme, whereas Glu-83, which belongs to the catalytic loop and is also critical for enzyme activity, is anchored to the divergent loop to maintain the active site open. In addition, we demonstrate that Cys-40 and Cys-168 are required for the interaction with CsTdx and that CsCyp binds the citrus carboxyl-terminal domain of RNA polymerase II YSPSAP repeat. Our data support a model where formation of the Cys-40-Cys-168 disulfide bond induces a conformational change that disrupts the interaction of the divergent and catalytic loops, via Glu-83, causing the active site to close. This suggests a new type of allosteric regulation in divergent cyclophilins, involving disulfide bond formation and a loop-displacement mechanism.

Patients' perceptions of participating in self-directed activities outside supervised occupational and physiotherapy within inpatient and home-based rehabilitation settings: a qualitative study.

PURPOSE: To investigate patients' perceptions of participating in self-directed activities, outside supervised occupational and physiotherapy, within rehabilitation settings. METHODS: Semi-structured interviews were undertaken with 16 patients and in three instances, their carers, from three health services in Victoria, Australia, two offering inpatient and one offering home-based rehabilitation care. A thematic analysis was performed using a framework approach. RESULTS: Themes identified included the role of the clinicians in encouraging patients and instilling confidence, giving feedback and "just being there"; considerations in program delivery, including different formats, support from peers and relatives, and program familiarity and flexibility; patients' different intrinsic driving and limiting forces, including following orders, seeing results, desiring autonomy and having an "inner athlete"; and the environment, including functional activities, space, equipment, time and availability. CONCLUSIONS: Patients and their carers reported positive experiences of participating in self-directed therapy programs within rehabilitation settings, with programs perceived as beneficial in optimising recovery. Patients reported a range of driving and limiting factors in relation to completing self-directed activities. Understanding these factors, relating to the patient, their environment and other people, is critical for clinicians so that they can modify their delivery accordingly, ensuring uptake and sustained implementation of self-directed activities in rehabilitation care.

Patients and their carers reported positive experiences of participating in self-directed therapy programs within rehabilitation settings.Self-directed therapy programs were seen to be beneficial in optimising recovery and helping patients return to previous levels of function.Understanding patients' specific driving and limiting factors in relation to completing self-directed activities, is critical for clinicians so that they can modify their delivery accordingly, ensuring uptake and sustained implementation of self-directed therapy in rehabilitation care.

A self-management program increases the dosage of inpatient rehabilitation by 26 minutes per day: a process evaluation.

PURPOSE: To evaluate the implementation of a self-management program, My Therapy, designed to increase inpatient rehabilitation therapy dosage via independent practice. MATERIALS AND METHODS: A process evaluation of My Therapy for adult patients admitted for rehabilitation for any condition supervised by physiotherapists and occupational therapists across eight rehabilitation wards compared usual care. Outcomes included reach, dosage, fidelity and adaptation. RESULTS: The mean (SD) age of the process evaluation sample (n = 123) was 73 (11) years with a mean (SD) length of stay of 14.0 (6.6) days. The My Therapy program reached 68% of participants (n = 632/928), and resulted in an average increase in therapy dosage of 26 (95% CI 12 to 40) minutes/day of independent practice. All My Therapy audited programs (n = 28) included body function/structure impairment-based exercises, and half (n = 13/28) included activity/participation-based exercises. On average, participants completed programs 1.8 (SD 1.2) times/day, which were prescribed in accordance with the My Therapy criteria, demonstrating fidelity. There were no between-group differences in daily steps or standing time, however, My Therapy participants spent more time sitting (p ≤ 0.05). Implementation adaptations were minimal. CONCLUSION: A self-management rehabilitation program was implemented with fidelity for two in three rehabilitation patients, resulting in increased therapy dosage with minimal adaptations.

The My Therapy self-management program was implemented with good reach (68% of participants received My Therapy) across four public and private inpatient rehabilitation services.Under My Therapy conditions, the dosage of inpatient rehabilitation therapy participation increased by an average of 26 minutes per day, which will help close the evidence-practice gap between the current rehabilitation dosage of about 1-hour per day, and the recommended rehabilitation dosage of 3-hours per day.My Therapy programs most frequently included impairment-based exercises that were completed in sitting, and did not increase time spent standing and walking.Consideration should be given to prescribing My Therapy (content and dosage) at an optimal level to promote patient functional independence, while maintaining safety.

Outcomes of the My Therapy self-management program in people admitted for rehabilitation: A stepped wedge cluster randomized clinical trial.

BACKGROUND: Self-management programs can increase the time spent on prescribed therapeutic exercises and activities in rehabilitation inpatients, which has been associated with better functional outcomes and shorter hospital stays. OBJECTIVES: To determine whether implementation of a self-management program ('My Therapy') improves functional independence relative to routine care in people admitted for physical rehabilitation. METHODS: This stepped wedge, cluster randomized trial was conducted over 54 weeks (9 periods of 6-week duration, April 2021 - April 2022) across 9 clusters (general rehabilitation wards) within 4 hospitals (Victoria, Australia). We included all adults (≥18 years) admitted for rehabilitation to participating wards. The intervention included routine care plus 'My Therapy', comprising a sub-set of exercises and activities from supervised sessions which could be performed safely, without supervision or assistance. The primary outcomes were the proportion of participants achieving a minimal clinically important difference (MCID) in the Functional Independence Measure, (FIM™) and change in total FIM™ score from admission to discharge. RESULTS: 2550 participants (62 % women) were recruited (control: n = 1458, intervention: n = 1092), with mean (SD) age 77 (13) years and 37 % orthopedic diagnosis. Under intervention conditions, participants reported a mean (SD) of 29 (21) minutes/day of self-directed therapy, compared to 4 (SD 14) minutes/day, under control conditions. There was no evidence of a difference between control and intervention conditions in the odds of achieving an MCID in FIM™ (adjusted odds ratio 0.93, 95 % CI 0.65 to 1.31), or in the change in FIM™ score (adjusted mean difference: -0.27 units, 95 % CI -2.67 to 2.13). CONCLUSIONS: My Therapy was delivered safely to a large, diverse sample of participants admitted for rehabilitation, with an increase in daily rehabilitation dosage. However, given the lack of difference in functional improvement with participation in My Therapy, self-management programs may need to be supplemented with other strategies to improve function in people admitted for rehabilitation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12621000313831), https://www.anzctr.org.au/.

Reforming allied health service provision in residential aged care to improve the rehabilitation reach: a feasibility study.

Objective My Therapy is an allied health guided, co-designed rehabilitation self-management program for residents of aged care facilities. This study aimed to determine the feasibility of implementing My Therapy in a residential aged care setting. Methods This observational study was conducted on a 30-bed wing, within a 90-bed metropolitan residential aged care facility, attached to a public health service, in Victoria, Australia. Staff and resident data were collected prospectively over 6 weeks (staff focus groups, patient surveys, and audits) to evaluate the feasibility domains of acceptability , reach and demand , practicality , integration , limited efficacy testing and adaptations . Results Twenty-six residents and five allied health staff (physiotherapy and occupational therapy) participated. My Therapy was acceptable to residents (survey) and staff (focus groups). Via initial My Therapy discussions between the resident and the therapists, to determine goals and resident preferences, My Therapy reached 26 residents (n = 26/26, 100% program reach ), with 15 residents subsequently receiving a rehabilitation program (n = 15/26, 58% program demand ). The remaining 11 residents did not participate due to resident preference or safety issues (n = 11/26, 42%). Collecting physical function outcome measures for limited efficacy testing was practical , and the cost of My Therapy was AUD$6 per resident per day, suggesting financial integration may be possible. Several adaptations were required, due to limited allied health staff, complex resident goal setting and program co-design. Conclusion My Therapy has the potential to improve the rehabilitation reach of allied health services in residential aged care. While introducing this low-cost intervention is feasible, adaptations were required for successful implementation.

The Legionella collagen-like protein employs a distinct binding mechanism for the recognition of host glycosaminoglycans.

Bacterial adhesion is a fundamental process which enables colonisation of niche environments and is key for infection. However, in Legionella pneumophila, the causative agent of Legionnaires' disease, these processes are not well understood. The Legionella collagen-like protein (Lcl) is an extracellular peripheral membrane protein that recognises sulphated glycosaminoglycans on the surface of eukaryotic cells, but also stimulates bacterial aggregation in response to divalent cations. Here we report the crystal structure of the Lcl C-terminal domain (Lcl-CTD) and present a model for intact Lcl. Our data reveal that Lcl-CTD forms an unusual trimer arrangement with a positively charged external surface and negatively charged solvent exposed internal cavity. Through molecular dynamics simulations, we show how the glycosaminoglycan chondroitin-4-sulphate associates with the Lcl-CTD surface via distinct binding modes. Our findings show that Lcl homologs are present across both the Pseudomonadota and Fibrobacterota-Chlorobiota-Bacteroidota phyla and suggest that Lcl may represent a versatile carbohydrate-binding mechanism.

The Legionella collagen-like protein employs a unique binding mechanism for the recognition of host glycosaminoglycans.

Bacterial adhesion is a fundamental process which enables colonisation of niche environments and is key for infection. However, in Legionella pneumophila, the causative agent of Legionnaires' disease, these processes are not well understood. The Legionella collagen-like protein (Lcl) is an extracellular peripheral membrane protein that recognises sulphated glycosaminoglycans (GAGs) on the surface of eukaryotic cells, but also stimulates bacterial aggregation in response to divalent cations. Here we report the crystal structure of the Lcl C-terminal domain (Lcl-CTD) and present a model for intact Lcl. Our data reveal that Lcl-CTD forms an unusual dynamic trimer arrangement with a positively charged external surface and a negatively charged solvent exposed internal cavity. Through Molecular Dynamics (MD) simulations, we show how the GAG chondroitin-4-sulphate associates with the Lcl-CTD surface via unique binding modes. Our findings show that Lcl homologs are present across both the Pseudomonadota and Fibrobacterota-Chlorobiota-Bacteroidota phyla and suggest that Lcl may represent a versatile carbohydrate binding mechanism.

NMR solution structure of a photoswitchable apoptosis activating Bak peptide bound to Bcl-xL.

The Bcl-2 family of proteins includes the major regulators and effectors of the intrinsic apoptosis pathway. Cancers are frequently formed when activation of the apoptosis mechanism is compromised either by misregulated expression of prosurvival family members or, more frequently, by damage to the regulatory pathways that trigger intrinsic apoptosis. Short peptides derived from the pro-apoptotic members of the Bcl-2 family can activate mechanisms that ultimately lead to cell death. The recent development of photocontrolled peptides that are able to change their conformation and activity upon irradiation with an external light source has provided new tools to target cells for apoptosis induction with temporal and spatial control. Here, we report the first NMR solution structure of a photoswitchable peptide derived from the proapoptotic protein Bak in complex with the antiapoptotic protein Bcl-x(L). This structure provides insight into the molecular mechanism, by which the increased affinity of such photopeptides compared to their native forms is achieved, and offers a rationale for the large differences in the binding affinities between the helical and nonhelical states.

Modulation of structure and dynamics by disulfide bond formation in unfolded states.

During oxidative folding, the formation of disulfide bonds has profound effects on guiding the protein folding pathway. Until now, comparatively little is known about the changes in the conformational dynamics in folding intermediates of proteins that contain only a subset of their native disulfide bonds. In this comprehensive study, we probe the conformational landscape of non-native states of lysozyme containing a single native disulfide bond utilizing nuclear magnetic resonance (NMR) spectroscopy, small-angle X-ray scattering (SAXS), circular dichroism (CD) data, and modeling approaches. The impact on conformational dynamics varies widely depending on the loop size of the single disulfide variants and deviates significantly from random coil predictions for both NMR and SAXS data. From these experiments, we conclude that the introduction of single disulfides spanning a large portion of the polypeptide chain shifts the structure and dynamics of hydrophobic core residues of the protein so that these regions exhibit levels of order comparable to the native state on the nanosecond time scale.

Understanding how small helical proteins fold: conformational dynamics of Im proteins relevant to their folding landscapes.

Understanding the mechanism of folding of small proteins requires characterization of their starting unfolded states and any partially unfolded states populated during folding. Here, we review what is known from NMR about these states of Im7, a 4-helix bundle protein that folds via an on-pathway intermediate, and show that there is an alignment of non-native structure in urea-unfolded Im7 with the helices of native Im7 that is a consequence of hydrophobic helix-promoting residues also promoting cluster-formation in the unfolded protein. We suggest that this kind of alignment is present in other proteins and is relevant to how native state topology determines folding rates.

Structural Model of a Porphyromonas gingivalis type IX Secretion System Shuttle Complex.

Porphyromonas gingivalis is a gram-negative oral anaerobic pathogen and is one of the key causative agents of periodontitis. P. gingivalis utilises a range of virulence factors, including the cysteine protease RgpB, to drive pathogenesis and these are exported and attached to the cell surface via the type IX secretion system (T9SS). All cargo proteins possess a conserved C-terminal signal domain (CTD) which is recognised by the T9SS, and the outer membrane ß-barrel protein PorV (PG0027/LptO) can interact with cargo proteins as they are exported to the bacterial surface. Using a combination of solution nuclear magnetic resonance (NMR) spectroscopy, biochemical analyses, machine-learning-based modelling and molecular dynamics (MD) simulations, we present a structural model of a PorV:RgpB-CTD complex from P. gingivalis. This is the first structural insight into CTD recognition by the T9SS and shows how the conserved motifs in the CTD are the primary sites that mediate binding. In PorV, interactions with extracellular surface loops are important for binding the CTD, and together these appear to cradle and lock RgpB-CTD in place. This work provides insight into cargo recognition by PorV but may also have important implications for understanding other aspects of type-IX dependent secretion.

INCLUDING EXERCISE SELF-MANAGEMENT AS PART OF INPATIENT REHABILITATION IS FEASIBLE, SAFE AND EFFECTIVE FOR PATIENTS WITH COGNITIVE IMPAIRMENT.

OBJECTIVE: To test the feasibility, safety and effectiveness of the My Therapy programme for inpatients with mild-moderate cognitive impairment. DESIGN: Observational pilot study. PATIENTS: Rehabilitation inpatients with mild-moderate cognitive impairment. METHODS: During their inpatient admission, participants received My Therapy, a programme that can increase the dose of rehabilitation through independent self-practice of exercises, outside of supervised therapy. Outcomes included My Therapy participation, falls, Functional Independence Measure (FIM) and 10-m walk test. Outcomes were compared with those of participants without cognitive impairment from the original My Therapy study (n = 116) using χ 2 and independent t-tests. RESULTS: Eight participants with mild-moderate cognitive impairment (mean (standard deviation (SD)) age 89.6 years (4.8); 3 women) were included. All participants completed the My Therapy programme on at least one day of their admission, with no associated falls. Participants had an 8.4 s (SD 5.1) reduction in their 10-m walk test and a 21.5 point (SD 11.1) improvement on FIM scores from admission to discharge. There were no significant between-group differences in feasibility, safety or effectiveness for participants with and without cognitive impairment. CONCLUSION: This pilot study has shown that including exercise self-management as part of inpatient rehabilitation is feasible, safe and effective for patients with cognitive impairment.

The role of large-scale motions in catalysis by dihydrofolate reductase.

Dihydrofolate reductase has long been used as a model system to study the coupling of protein motions to enzymatic hydride transfer. By studying environmental effects on hydride transfer in dihydrofolate reductase (DHFR) from the cold-adapted bacterium Moritella profunda (MpDHFR) and comparing the flexibility of this enzyme to that of DHFR from Escherichia coli (EcDHFR), we demonstrate that factors that affect large-scale (i.e., long-range, but not necessarily large amplitude) protein motions have no effect on the kinetic isotope effect on hydride transfer or its temperature dependence, although the rates of the catalyzed reaction are affected. Hydrogen/deuterium exchange studies by NMR-spectroscopy show that MpDHFR is a more flexible enzyme than EcDHFR. NMR experiments with EcDHFR in the presence of cosolvents suggest differences in the conformational ensemble of the enzyme. The fact that enzymes from different environmental niches and with different flexibilities display the same behavior of the kinetic isotope effect on hydride transfer strongly suggests that, while protein motions are important to generate the reaction ready conformation, an optimal conformation with the correct electrostatics and geometry for the reaction to occur, they do not influence the nature of the chemical step itself; large-scale motions do not couple directly to hydride transfer proper in DHFR.

Site-specific investigation of the steady-state kinetics and dynamics of the multistep binding of bile acid molecules to a lipid carrier protein.

The investigation of multi-site ligand-protein binding and multi-step mechanisms is highly demanding. In this work, advanced NMR methodologies such as 2D (1)H-(15)N line-shape analysis, which allows a reliable investigation of ligand binding occurring on micro- to millisecond timescales, have been extended to model a two-step binding mechanism. The molecular recognition and complex uptake mechanism of two bile salt molecules by lipid carriers is an interesting example that shows that protein dynamics has the potential to modulate the macromolecule-ligand encounter. Kinetic analysis supports a conformational selection model as the initial recognition process in which the dynamics observed in the apo form is essential for ligand uptake, leading to conformations with improved access to the binding cavity. Subsequent multi-step events could be modelled, for several residues, with a two-step binding mechanism. The protein in the ligand-bound state still exhibits a conformational rearrangement that occurs on a very slow timescale, as observed for other proteins of the family. A global mechanism suggesting how bile acids access the macromolecular cavity is thus proposed.