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Background There is a need to evaluate if and how telerehabilitation approaches might co-exist within healthcare in the long-term. Our aim was to implement and evaluate a multidisciplinary group-based telerehabilitation approach for people engaging in neurological rehabilitation. Methods NeuroRehabilitation OnLine (NROL) was adapted and implemented within an existing healthcare system as a programme of repeating six-week blocks. A robust evaluation was undertaken simultaneously using a convergent parallel design underpinned by implementation frameworks. This included service data, and patient and staff interviews. Implementation success was conceptualised using the outcomes of appropriateness, acceptability and sustainability. Results Eight NROL blocks delivered 265 sessions with 1347 patient contacts, and NROL continues as part of standard practice. The approach was appropriate for varied demographics and had positive patient opinions and outcomes for many. Staff perceived NROL provided a compatible means to increase therapy and help meet targets, despite needing to mitigate some challenges when fitting the approach within the existing system. NROL was considered acceptable due to good attendance (68%), low drop-out (12%), and a good safety record (one non-injury fall). It was accepted as a new way of working across rehabilitation disciplines as an ‘extra layer of therapy’. NROL had perceived advantages in terms of patient and staff resource (e.g. saving time, energy and travel). NROL provided staffing efficiencies (ratio 0.6) compared to one-to-one delivery. Technology difficulties and reluctance were surmountable with dedicated technology assistance. Leadership commitment was considered key to enable the efforts needed for implementation and sustained use. Conclusion Pragmatic implementation of group-based telerehabilitation was possible as an adjunct to neurological rehabilitation within an existing healthcare system. The compelling advantages reported of having NROL as part of rehabilitation supports the continued use of this telerehabilitation approach. This project provides an exemplar of how evaluation can be run concurrently with implementation, applying a data driven rather than anecdotal approach to implementation.

Transforming Growth Factor--beta (TGFβ) superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs), and Bone Morphogenetic Proteins (BMPs), are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer), to engineer chemically-refoldable TGFβ superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-βA and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGFβ superfamily ligands through development of novel chimeric TGFβ ligands with diverse biological and clinical values.

Background and Objective Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug–drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H 2 -receptor antagonist; both NCT01539655). Methods Four open-label, phase I studies were conducted in healthy volunteers: n  = 14 (metformin), n  = 14 (digoxin), n  = 17 (midazolam), n  = 16 (omeprazole), n  = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1–4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. Results Vandetanib + metformin increased metformin area under the plasma concentration–time curve from zero to infinity (AUC 0–∞ ) and maximum observed plasma concentration (C max ) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CL R ) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC 0–last ) and C max by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CL R . Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. Conclusion Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug–drug interactions.

Background: Psychological problems post-stroke can negatively impact stroke survivors. Although general psychological services exist (e.g., NHS Talking Therapies), access remains limited, particularly for individuals with post-stroke communication and cognitive impairments. Stroke service staff report low confidence in managing psychological distress. This study is the first to explore the barriers and facilitators to implementing a novel intervention package comprising a cross-service care pathway and staff training to enhance post-stroke psychological provision. Methods: Staff from stroke and mental health services in four UK regions, recruited through purposive sampling to ensure diversity of services and professional roles, participated in semi-structured interviews or focus groups, guided by the Theoretical Domains Framework (TDF), before and after implementation of the intervention package. Pre-implementation interviews/groups identified anticipated barriers and facilitators to implementation and training needs, informing the development of site-specific intervention packages; post-implementation interviews/groups explored experienced barriers, facilitators and perceptions of the intervention. Interviews underwent thematic analysis using the TDF. Results: Fifty-five staff participated pre-implementation and seventeen post-implementation, representing stroke (e.g., nurse, physiotherapist, consultant) and psychology (e.g., counsellor, psychological therapist) roles across acute, rehabilitation, community, and voluntary services. Challenges anticipated pre-implementation included: limited specialist post-stroke psychological support; low staff confidence; and fragmented service pathways. Post-implementation findings indicated increased staff knowledge and confidence, enhanced screening and referral processes, and stronger inter-service collaboration. Implementation success varied across sites (with some sites showing greater ownership and sustainability of the intervention) and across staff roles (with therapy staff more likely than nursing staff to have received training). Conclusions: Effective implementation of an intervention package to increase psychological provision post-stroke requires staff engagement at all levels across all services. Staff investment influenced ownership of the intervention package, beliefs about priorities and overall enhancement of service capability.

Transforming Growth Factor - beta (TGF[beta]) superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs), and Bone Morphogenetic Proteins (BMPs), are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer), to engineer chemically-refoldable TGF[beta] superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-[beta]A and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGF[beta] superfamily ligands through development of novel chimeric TGF[beta] ligands with diverse biological and clinical values.

Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22–1·10]; d=0·46 [0·16–0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

Background To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. Methods Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib ± docetaxel), ZEAL ( NCT00418886 , vandetanib ± pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. Results The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3–1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n  = 3; comparator, n  = 4). 2.8% ( n  = 26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in > 10% of tumor cells), 8.1% ( n  = 76) had low RET gene copy number gain (4–6 copies in ≥40% of tumor cells) and 8.3% ( n  = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET -rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. Conclusions We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation. Trial registration Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR).

Background: Psychological problems post-stroke are common and debilitating, yet insufficient evidence-based psychological support exists for stroke survivors, either in stroke or general mental health services. Many stroke survivors with significant needs remain unsupported. To address this problem, we need pathways to identify, treat and manage psychological difficulties after stroke. The Accelerating Delivery of Psychological Therapies after Stroke (ADOPTS) study aimed to explore the feasibility of collaboratively developing, implementing and evaluating intervention packages (IPs) to facilitate access to, and increase the provision of, psychological support post-stroke. Methods: Stakeholder groups were formed across four sites in north-west England, comprising stroke and psychological services, to collaboratively develop site-specific IPs incorporating a psychological care pathway, staff training, a staff manual for stroke-specific psychological support and supervision. A feasibility stepped-wedge cluster randomised trial recruited patients admitted with stroke during the usual care (pre-implementation of the IP) and intervention (post-implementation) periods. The feasibility of IP implementation and their potential usefulness were evaluated through assessing wellbeing and the support received, and through a process evaluation incorporating interviews with staff, patients and carers. Feasibility evaluation included the recruitment rate and attrition rate; exploratory analysis (mixed-effects linear or logistic regression models) was used to assess the ‘promise’ of the intervention in achieving psychological distress outcomes (mood (PHQ-9), anxiety (GAD-7)), assessed using validated measures at 6 weeks and 6 months. Results: IPs were collaboratively developed at each site but implementation took longer than the per-study-protocol duration of three months. Nineteen training sessions (152 attendees) were delivered for nursing, therapy, NHS Talking Therapies and voluntary staff. Nursing staff were underrepresented due to difficulties with releasing staff. Manuals were developed for each site, incorporating a mood screening and referral algorithm, but these were not finalised at one site. Stroke and NHS Talking Therapies champions were identified in each site to facilitate cross-service staff supervision. A total of 270 patients were recruited over 14 months (133 usual care, 137 intervention), with 227 and 198 at 6 weeks and 6 months, respectively. Stroke staff found the training, manual and pathway helpful, and reported greater confidence in managing and referring psychological issues. NHS Talking Therapies staff found the training useful for adapting their therapy. However, the intervention took longer to implement in all sites, requiring an additional time period to be added to the stepped-wedge design. Conclusions: It is feasible to collaboratively develop and implement IPs for post-stroke psychological support. However, an alternative to the stepped-wedge design used here would be more appropriate for a future study. This study was registered in ISRCTN—the UK’s Clinical Study Registry (trial registration: ISRCTN12868810, registration date: 4 February 2016).

Background and Objective Vandetanib, an oncology drug being evaluated in phase III clinical trials, undergoes significant renal and hepatic excretion. The objective of these two studies was to investigate the single-dose pharmacokinetics of vandetanib in subjects with renal or hepatic impairment in comparison with healthy subjects. Subjects and Methods Two open-label, parallel-group studies were conducted at a single centre in Germany. Subjects aged 18-75 years with a body mass index of 18–32 kg/m2 were eligible. The renal impairment study recruited subjects with normal renal function and mild, moderate and severe renal impairment according to creatinine clearance calculated from a 24-hour urine collection pre-dose. The hepatic impairment study recruited subjects with normal hepatic function and mild, moderate and severe hepatic impairment according to the Child-Pugh classification. All subjects received a single 800mg oral vandetanib dose. Blood samples for measurement of vandetanib, N -desmethylvandetanib and vandetanib N -oxide were collected before and at various timepoints after vandetanib administration for up to 63 days. Pharmacokinetic parameters were determined using noncompartmental methods. Results Thirty-two subjects were recruited for the renal impairment study (ten with normal renal function and six, ten and six with mild, moderate and severe impairment, respectively). Thirty subjects were recruited for the hepatic impairment study (eight with normal hepatic function and eight, eight and six with mild, moderate and severe impairment, respectively). The area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) values of free vandetanib increased by approximately 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. These increases were statistically significant, with the increase in the severe renal impairment group having the possibility of being double the value observed in subjects with normal renal function (geometric least squares [GLS] mean ratio [renal impairment: normal renal function] of 1.79; 90% CI 1.39, 2.31). Peak plasma concentrations of free vandetanib increased slightly by approximately 7%, 9% and 11% in subjects with mild, moderate and severe renal impairment, respectively. Total plasma clearance of free vandetanib decreased with all degrees of renal dysfunction. Hepatic impairment did not have a statistically significant effect on the AUC ∞ of total vandetanib. Peak plasma concentrations of total vandetanib were reduced in subjects with all classifications of hepatic impairment compared with normal hepatic function, with a statistically significant effect in the severe hepatic impairment group (GLS mean ratio 0.71; 90% CI 0.53, 0.96). Increased exposure to both metabolites was seen in subjects with renal impairment. Exposure to N -desmethylvandetanib was reduced in subjects with hepatic impairment, while exposure to vandetanib N -oxide was increased in subjects with severe hepatic impairment. Vandetanib was well tolerated and had a similar tolerability profile in subjects with renal or hepatic impairment compared with healthy subjects. Conclusion Exposure to vandetanib was increased by about 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. A doubling in exposure could be ruled out in subjects with mild or moderate renal impairment but not for those with severe renal impairment. The possibility of dose reductions in patients with severe renal impairment will need to be assessed when the safety and tolerability profile is fully defined. Exposure to vandetanib was not altered in subjects with hepatic impairment, and no dose adjustment would be expected in patients with hepatic impairment.