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To investigate the sustainability of Robot-assisted upper limb therapy (RT-UL) as part of routine occupational therapy and physiotherapy clinical practice. Two separate audits, 12 months apart, of RT-UL computer data records were undertaken to determine sustainability in a subacute rehabilitation unit. Records of the two audits were compared in terms of the number of early subacute stroke survivors using RT-UL, the number of RT-UL sessions, duration of RT-UL sessions, and disciplines prescribing RT-UL. During Audit 1 58% (n = 18) of stroke survivors received RT-UL compared to 50% (n = 7) in Audit 2. The total number of RT-UL sessions reduced between audits (148 vs. 36 sessions) reflecting the overall reduction in admission rates for stroke survivors. There was no significant difference between audits in the average number of RT-UL sessions per patient (p = 0.203) nor the length of sessions (p = 0.762). Patients engaged in active therapy more than three-quarters of the time when on the robotic device. Physiotherapists were the primary prescribers of RT-UL when compared to occupational therapists. RT-UL was in continued and regular use with stroke survivors 2 years after initial implementation within an inpatient rehabilitation setting. RT-UL practice was intensive and used routinely with patients. RT-UL is a sustainable and intensive intervention for stroke survivors within an inpatient rehabilitative setting. The cost-benefits of RT-UL should be evaluated from the perspective of the whole rehabilitation service not just at an individual patient level. RT-UL may be considered a "bridging" form of UL practice for those with more limited active UL movement until there is sufficient UL movement and power for more complex real-world task-specific practice. [ABSTRACT FROM AUTHOR]

Robot assisted upper limb (UL) therapy has been identified as an intervention with the potential to help improve the amount of practice performed by stroke survivors. This study aimed to measure the amount of UL practice (i.e., repetitions, duration, intensity) performed by subacute stroke survivors, in particular those with severe UL impairment, pre and post implementation of robot assisted upper limb therapy (RT-UL) into an inpatient rehabilitation setting. Two observational study phases (pre-RT-UL and post-RT-UL) were undertaken of occupational therapy and physiotherapy sessions performed by subacute stroke survivors. Upper limb tasks observed and recorded in therapy were classified as either impairment-related therapy or activity-related. In the pre-RT-UL observational phase, 7 subacute stroke survivors were observed across 11 days involving 25 therapy sessions. Post-RT-UL, 12 subacute stroke survivors were observed across 12 days involving 29 therapy sessions. There were no significant differences in characteristics of patients observed in each phase (p >.05). The mean difference (95% CI) between pre and post RT-UL for repetitions (reps) (569 (1 to 1136) and intensity (7 (4–11)) reps/min of practice increased for all patients, including those with severe UL impairment (337 (37–638)) reps and 8 (2–14) reps/minute, with the duration of therapy unchanged. This is the first study to have observed an increase in UL practice with the inclusion of RT-UL as part of routine clinical practice. This increase in practice is considered to be due to RT-UL providing highly supportive and expeditious semi-supervised practice. Notably, RT-UL was able to be implemented within the existing organisational structures with only basic training of therapy staff. Robotics presents as a viable intervention to increase the amount and intensity of upper limb practice performed by stroke survivors in routine clinical practice Robotics were able to be implemented within the existing organisational structures with only basic training of therapy staff [ABSTRACT FROM AUTHOR]

Advancement of therapeutic protein therapies can be hindered by their poor stability and short in vivo half‐life. There is emerging evidence that biocompatible zwitterionic materials can prevent nonspecific interactions within proteins systems that contribute to protein instability. Here, zwitterionic hydrogel beads are synthesized from poly(sulfobetaine methyl methacrylate), pSB, using an inverse emulsion, free radical polymerization reaction technique. The transport properties within the zwitterionic hydrogels were characterized using 1H NMR diffusometry. Equilibrium water content as high as 0.90 was measured for the synthesized hydrogels. Our study revealed that the pSB hydrogels are nontoxic, ion responsive, and their swelling is temperature dependent. The zwitterionic hydrogel beads were capable of undergoing lyophilization without aggregation. Hydrogel beads were loaded with a model protein, bovine serum albumin (BSA), using a postfabrication loading technique. The protein loading was studied using confocal laser microscopy, indicating homogenous protein dispersion of up to 40 μg BSA/mg hydrogel within the beads. Furthermore, the release rate of the protein from the synthesized hydrogel was studied at different crosslinker to monomer ratios. The protein encapsulated within the zwitterionic hydrogel had slower rates of thermal aggregation compared to nonencapsulated protein in solution. Furthermore, the protein‐loaded inside the zwitterionic hydrogel better maintained its bioactivity. [ABSTRACT FROM AUTHOR]

Therapeutic proteins are utilized in a variety of clinical applications, but side effects and rapid in vivo clearance still present hurdles. An approach that addresses both drawbacks is protein encapsulation within in a polymeric nanoparticle, which is effective but introduces the additional challenge of destabilizing the nanoparticle shell in clinically relevant locations. This study examined the effects of crosslinking self‐assembled poly(l‐lysine)‐grafted‐poly(ethylene glycol) nanoparticles with redox‐responsive 3,3′‐dithiobis(sulfosuccinimidyl propionate) (DTSSP) to achieve nanoparticle destabilization in a reductive environment. The polymer‐protein nanoparticles (DTSSP NPs) were formed through electrostatic self‐assembly and crosslinked with DTSSP, which contains a glutathione‐reducible disulfide. As glutathione is upregulated in various cancers, DTSSP NPs could display destabilization within cancer cells. A library of DTSSP NPs was formed with varying copolymer to protein (C:P) and crosslinker to protein (X:P) mass ratios and characterized by size and encapsulation efficiency. DTSSP NPs with a 7:1 C:P ratio and 2:1 X:P ratio were further characterized by stability in the presence proteases and reducing agents. DTSSP NPs fully encapsulated the model protein and displayed 81% protein release when incubated with 5 mM dithiothreitol for 12 hr. This study contributes to understanding stimulus‐responsive crosslinking of polymeric nanoparticles and could be foundational to clinical administration of therapeutic proteins. [ABSTRACT FROM AUTHOR]

Introduction: Robot‐assisted therapy for the upper limb (RT‐UL) is an emerging form of intervention for stroke survivors with upper limb deficits. However, there is limited knowledge regarding therapists' perceptions of RT‐UL and the factors influencing the implementation of RT‐UL into the clinical setting. This is important when considering that therapists in Australia are primarily responsible for the prescription of RT‐UL in daily practice. This study aimed to explore occupational therapists' and physiotherapists' perceptions of RT‐UL and the perceived barriers and enablers influencing implementation. Methods: Two discipline‐specific focus groups were conducted involving occupational therapists (n = 6) and physiotherapists (n = 6). Participants were members of the same multidisciplinary team working in an Australian public health rehabilitation facility where RT‐UL (i.e. InMotion2) was being introduced for the first time. Focus groups explored therapist perceptions of the new RT‐UL as well as perceived barriers and enablers to implementation. Focus groups were recorded, transcribed and deductively analysed using the Theoretical Domains Framework (TDF). Results: Out of the 14 domains of the TDF, 7 were raised by participants during the focus groups: environmental context and resources, beliefs about consequences, optimism, knowledge, skills, social influences, and social and professional role and identity. Therapists' expressed their optimism towards the introduction of RT‐UL but believed successful implementation would be primarily dependent on the availability of clinical leadership, training and a suitable client mix. Conclusion: Therapists perceived that RT‐UL would provide opportunity for increased upper limb practice particularly for patients with severe upper limb impairment. To facilitate implementation, support of RT‐UL should come from both management and clinical leaders and training include RT‐UL efficacy, device functionality and patient suitability. The availability of a single RT‐UL device in a workplace may create unique interdisciplinary and logistical challenges. [ABSTRACT FROM AUTHOR]

This article examines the perception of the (ing) variants, [ɪŋ] and [ɪn], in three regionally distinct localities in Britain: London in the South of England; Manchester in the North; and Edinburgh in Scotland. Data was gathered in perceptual tests in which respondents from each location rated stimuli doublets, each containing only one of the variants of (ing), on multiple social attribute scales. In London and Manchester, the perception of [ɪŋ] and [ɪn] broadly matches findings made for the United States in that speakers using [ɪŋ] are considered more articulate and hardworking, and less casual than speakers using [ɪn]. In Edinburgh, results are markedly different. We argue that these differences are due to a combination of factors that include the historical development of (ing) in a particular locale, which led to differences in production, variations in language ideology and, as a result, class-specific evaluations that appear to be regionally dependent. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate a library of poly- l -lysine (PLL)-graft (g)-polyethylene glycol (PEG) copolymers for the ability to encapsulate effectively a model protein, bovine serum albumin (BSA), and to characterize the stability and protein function of the resulting nanoparticle. A library of nine grafted copolymers was produced by varying PLL molecular weight and PEG grafting ratio. Electrostatic self-assembly of the protein and the grafted copolymer drove encapsulation. The formation of protein/polymer nanoparticles with a core/shell structure was confirmed using PAGE, dynamic light scattering, and electron microscopy. Encapsulation of the BSA into nanoparticles was strongly dependent on the copolymer-to-protein mass ratio, PEG grafting ratio, and PLL molecular weight. A copolymer-to-protein mass ratio of 7:1 and higher was generally required for high levels of encapsulation, and under these conditions, no loss of protein activity was observed. Copolymer characteristics also influenced nanoparticle resistance to polyanions and protease degradation. The results indicate that a copolymer of 15–30 kDa PLL, with a PEG grafting ratio of 10:1, is most promising for protein delivery. [ABSTRACT FROM AUTHOR]

This study examines the social meanings that speakers associate with variants of the variable (ing) in Manchester, focusing on a comparison of two age groups: a young age group of adolescents and those in very early adulthood, and an older age group. In most English varieties, (ing) has two possible realisations: [In] and [In]. However, in Manchester, a third possibility exists: [Ing]. Social meanings differ between age groups on three scales: articulateness, poshness and reliability. When compared to the youths, those in the older age group consider [In] to sound substantially more articulate than [In], as well as posher and more reliable than [Ing]. In contrast, those in the younger group consider [Ing] more reliable and posher-sounding than the older speakers. This is due, we argue, to developmental constraints during adolescence, but, more importantly, to life-stage experiences, with social meanings on these three scales altering as speakers leave adolescence behind and become increasingly subject to the standardisation pressures of adult communities. [ABSTRACT FROM AUTHOR]

We previously reported that recombinant human butyrylcholinesterase (rhBChE) complexed with a series of copolymers of poly- l -lysine (PLL) with grafted (polyethylene) glycol (PEG) (i.e., PLL-g-PEG) showed reduced catalytic activity but relatively similar concentration-dependent inactivation of the organophosphorus inhibitor paraoxon. Herein, we compared the kinetics of catalysis (using butyrylthiocholine as the substrate) and inhibition (using four different inhibitors) of free and copolymer-complexed rhBChE. Using scanning electron microscopy, polyionic complexes of rhBChE with three different PLL-g-PEG copolymers (based on PLL size) appeared as spheroid-shaped particles with relatively similar particle sizes (median diameter = 35 nm). Relatively similar particle sizes were also noted using dynamic light scattering (mean = 26–35 nm). The three copolymer-complexed enzymes exhibited reduced k cat (30–33% reduction), but no significant changes in K m . Inhibitory potency (as reflected by the bimolecular rate constant, k i ) was similar among the free and copolymer-complexed enzymes when paraoxon was the inhibitor, whereas statistically significant reductions in k i (16–60%) were noted with the other inhibitors. Sensitivity to inactivation by proteases and heat was also compared. Copolymer-complexed enzymes showed lesser time-dependent inactivation by the proteases trypsin and pronase and by heat compared to the free enzyme. Understanding the unique properties of PLL-g-PEG-BChE complexes may lead to enhanced approaches for use of BChE and other protein bioscavengers. [ABSTRACT FROM AUTHOR]

Reducing the promiscuous tropism of native adenovirus by using fiberless adenovirus is advantageous toward its use as a gene therapy vector or vaccine component. The removal of the fiber protein on native adenovirus abrogates several undesirable interactions; however, this approach decreases the particle's physical stability. To create stable fiberless adenovirus for pharmaceutical use, the effects of temperature and pH on the particle's stability profile must be addressed. Our results indicate that the stability of fiberless adenovirus is increased when it is stored in mildly acidic conditions around pH 6. The stability of fiberless adenovirus can be further enhanced by using excipients. Excipient screening results indicate that the nonionic surfactant Pluronic F-68 and the amino acid glycine are potential stabilizers because of their ability to increase the thermal transition temperature of the virus particle and promote retention of biological activity after exposure to prolonged thermal stress. Our data indicate that the instability of fiberless adenovirus can be ameliorated by storing the virus in the appropriate environment, and it should be possible to further optimize the virus so that it can be used as a biopharmaceutical. [ABSTRACT FROM AUTHOR]

Background Adenovirus (Ad) is one of the viral vectors most widely used for gene delivery. The virus, however, has serious shortcomings such as immunogenicity, promiscuous tropism, and the inability to efficiently infect certain types of cells. The goal of this study was to improve the ability of an Ad-based vector to efficiently transform cells that lack the native coxsackie-adenovirus receptor (CAR − ) by modifying the virus with CPP-PEG conjugates. Methods The vector was produced by PEGylating Ad, which packages a lacZ reporter gene, and then conjugating CPPs to form CPP-PEG-Ad particles. The study compared the effectiveness of four different CPPs: Pen, Tat, Pep1, and pArg. The effects of CPP amount per virus, degree of PEGylation, and PEG molecular weight on transduction efficiency were studied on CAR − NIH/3T3 cells. Results CPP-PEG-Ad particles transduced CAR − cells significantly better than unmodified Ad. Pen, the most effective CPP, produced an 80-fold improvement in transduction compared to the unmodified virus. The Pen peptide utilized a combination of electrostatic and hydrophobic interactions with the cell membrane to maximize cellular association while the other CPPs used only electrostatic or hydrophobic interactions but not both. Lastly, higher degrees of PEGylation, which prompted PEG to adopt a “brush” conformation, resulted in more efficient CPP-PEG-Ad particles because of both better conjugation of CPPs to the PEGylated virus and better exposure of the conjugated CPPs on the surface of the particle. Conclusions CPP-PEG-Ad particles efficiently deliver genes to cells that Ad alone would not efficiently infect, thereby extending potential gene therapy treatments to a much broader range of cell types and diseases. [ABSTRACT FROM AUTHOR]

Introduction: Robotic-assisted knee replacement systems have been introduced to healthcare services worldwide in an effort to improve clinical outcomes for people, although high-quality evidence that they are clinically, or cost-effective remains sparse. Robotic-arm systems may improve surgical accuracy and could contribute to reduced pain, improved function and lower overall cost of total knee replacement (TKR) surgery. However, TKR with conventional instruments may be just as effective and may be quicker and cheaper. There is a need for a robust evaluation of this technology, including cost-effectiveness analyses using both within-trial and modelling approaches. This trial will compare robotic-assisted against conventional TKR to provide high-quality evidence on whether robotic-assisted knee replacement is beneficial to patients and cost-effective for healthcare systems., Methods and Analysis: The Robotic Arthroplasty Clinical and cost Effectiveness Randomised controlled trial-Knee is a multicentre, participant-assessor blinded, randomised controlled trial to evaluate the clinical and cost-effectiveness of robotic-assisted TKR compared with TKR using conventional instruments. A total of 332 participants will be randomised (1:1) to provide 90% power for a 12-point difference in the primary outcome measure; the Forgotten Joint Score at 12 months postrandomisation. Allocation concealment will be achieved using computer-based randomisation performed on the day of surgery and methods for blinding will include sham incisions for marker clusters and blinded operation notes. The primary analysis will adhere to the intention-to-treat principle. Results will be reported in line with the Consolidated Standards of Reporting Trials statement. A parallel study will collect data on the learning effects associated with robotic-arm systems., Ethics and Dissemination: The trial has been approved by an ethics committee for patient participation (East Midlands-Nottingham 2 Research Ethics Committee, 29 July 2020. NRES number: 20/EM/0159). All results from the study will be disseminated using peer-reviewed publications, presentations at international conferences, lay summaries and social media as appropriate., Trial Registration Number: ISRCTN27624068., Competing Interests: Competing interests: Stryker is providing funding for consumables, preoperative CT costs and 10 min of theatre time, according to contractual arrangements. They also fund some postoperative CT costs in the learning effects study. Appropriate contracts are in place to ensure the independence of the trial team with regard to study design, data collection, management, analysis and interpretation in line with NIHR reporting standards. Multiple investigators are investigators on two other NIHR-funded studies receiving additional support for treatment costs from Stryker, START:REACTS (16/61/18) (AM, HP, CEH, JM and MU) and RACER-Hip (NIHR131407) (AM, ETD, HP, SR, CEH, DRE, JM, FSH, JAS and MU). The full independence of the investigators of these related studies are protected by legal agreements, similar to this study. FSH receives funding from Stryker to run clinical studies. Multiple authors report other unrelated research grants from NIHR during the conduct of the study. DRE, HP and JG are supported from NIHR Research Capability Funding via University Hospitals Coventry and Warwickshire. MU is chief investigator or coinvestigator on multiple previous and current research grants from the UK National Institute for Health Research, Arthritis Research UK and is a coinvestigator on grants funded by the Australian NHMRC and Norwegian MRC. He was an NIHR Senior Investigator until March 2021. He has received travel expenses for speaking at conferences from the professional organisations hosting the conferences. He is a director and shareholder of Clinvivo that provides electronic data collection for health services research. He is part of an academic partnership with Serco Ltd, funded by the European Social Fund, related to return to work initiatives. Until March 2020 he was an editor of the NIHR journal series, and a member of the NIHR Journal Editors Group, for which he received a fee., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Red blood cells (RBCs) express a variety of immunomodulatory markers that enable the body to recognize them as self. We have shown that RBC membrane glycophorin A (GPA) receptor can mediate membrane attachment of protein therapeutics. A critical knowledge gap is whether attaching drug-encapsulated nanoparticles (NPs) to GPA and modification with cell-penetrating peptide (CPP) will impact binding, oxygenation, and the induction of cellular stress. The objective of this study was to formulate copolymer-based NPs containing model fluorescent-tagged bovine serum albumin (BSA) with GPA-specific targeting ligands such as ERY1 (ENPs), single-chain variable antibody (scFv TER-119, SNPs), and low-molecular-weight protamine-based CPP (LNPs) and to determine their biocompatibility using a variety of complementary high-throughput in vitro assays. Experiments were conducted by coincubating NPs with RBCs at body temperature, and biocompatibility was evaluated by Raman spectroscopy, hemolysis, complement lysis, and oxidative stress assays. Data suggested that LNPs effectively targeted RBCs, conferring 2-fold greater uptake in RBCs compared to ENPs and SNPs. Raman spectroscopy results indicated no adverse effect of NP attachment or internalization on the oxygenation status of RBCs. Cellular stress markers such as glutathione, malondialdehyde, and catalase were within normal limits, and complement-mediated lysis due to NPs was negligible in RBCs. Under the conditions tested, our data demonstrates that molecular targeting of the RBC membrane is a feasible translational strategy for improving drug pharmacokinetics and that the proposed high-throughput assays can prescreen diverse NPs for preclinical and clinical biocompatibility.