Designing clinical trials in older people.

Adequate medical care of the increasingly ageing population requires robust clinical trial data both to inform treatment decisions, and to understand the natural history of diseases which primarily affect the elderly. However, this information is widely lacking, which is likely to have significant clinical consequences. Under-representation of older people in clinical trials is well documented, the reasons including physicians' perception, protocol eligibility criteria, and functional status requirements. Many clinical trial designs remain conservative and there is no established standardised methodology for recruiting more elderly patients with co-morbidities and disability into clinical trials. Designing clinical trials in older people poses a unique set of challenges, particularly regarding recruitment, retention and data analysis. In this review we outline the difficulties encountered in conducting clinical trials in older patients and describe some of the initiatives that can be put in place to counteract them. It is only by addressing these challenges with careful and adequately resourced protocol design that clinical trials may successfully address the therapeutic questions raised by our ageing population

Reversal of parkinsonian symptoms in primates by antagonism of excitatory amino acid transmission: potential mechanisms of action.

Parkinsonism is characterised by overactive glutamatergic transmission in the cortico-striatal and subthalamo-medial pallidal pathways. Local blockade of glutamatergic transmission in these pathways can alleviate parkinsonian symptoms. The effectiveness of the treatment, however, is often limited by the simultaneous appearance of unwanted side-effects. These side-effects, including ataxia and dissociative anaesthesia, are particularly problematic when N-methyl-D-aspartate (NMDA) antagonists are used. In an attempt to overcome these problems we have attempted to manipulate excitatory amino acid (EAA)-mediated neurotransmission indirectly by targeting the NMDA receptor associated modulatory sites. We review evidence which demonstrates that antagonists for both the NMDA associated glycine and polyamine sites can reverse parkinsonian symptoms when injected intra-cerebrally in both MPTP-treated and bilateral 6-OHDA lesioned marmosets without eliciting unwanted side-effects. We further review preliminary data which suggest that ifenprodil, a polyamine site antagonist, has striking anti-parkinsonian actions in the marmoset. Potential mechanisms of action underlying these effects are discussed in terms of NMDA receptor subtypes and the neuroanatomical locus of action. The anti-parkinsonian efficacy of intra-striatally administered EAA antagonists leads us to question the view of dopamine acting in the striatum as a simple neuromodulator

The feminisation of British neurology: implications for workforce planning.

As in other hospital specialties, an increasing proportion of neurology trainees are female. To predict the workforce implications it is necessary to determine what life choices future neurologists will make. A questionnaire survey of life choices was administered to neurology consultants and trainees, general medical senior house officers, and medical students. Of the 344 respondents, 3% of specialist registrars (SpRs) and 4.6% of consultants work part time. Eighty-seven per cent of female and 22% of male junior doctors plan to work part time for, on average, 7.5 and 1.5 years respectively. Thirty percent of consultants also plan to work part time. A number of SpRs (14.3%) and consultants (6%) have taken a career break while 37.5% of SpRs and 18.2% of consultants are planning a career break. The changing demands of both sexes will have a greater impact on the neurology workforce than the increasing proportion of women alone. Increased part-time working will require additional trainees to ensure service requirements are met

A modular, deep learning-based holistic intent sensing system tested with Parkinson’s disease patients and controls

Copyright \ua9 2023 Russell, Inches, Carroll and Bergmann.People living with mobility-limiting conditions such as Parkinson’s disease can struggle to physically complete intended tasks. Intent-sensing technology can measure and even predict these intended tasks, such that assistive technology could help a user to safely complete them. In prior research, algorithmic systems have been proposed, developed and tested for measuring user intent through a Probabilistic Sensor Network, allowing multiple sensors to be dynamically combined in a modular fashion. A time-segmented deep-learning system has also been presented to predict intent continuously. This study combines these principles, and so proposes, develops and tests a novel algorithm for multi-modal intent sensing, combining measurements from IMU sensors with those from a microphone and interpreting the outputs using time-segmented deep learning. It is tested on a new data set consisting of a mix of non-disabled control volunteers and participants with Parkinson’s disease, and used to classify three activities of daily living as quickly and accurately as possible. Results showed intent could be determined with an accuracy of 97.4% within 0.5 s of inception of the idea to act, which subsequently improved monotonically to a maximum of 99.9918% over the course of the activity. This evidence supports the conclusion that intent sensing is viable as a potential input for assistive medical devices

Impact of digital technologies on self-efficacy in people with Parkinson\u27s: a scoping review protocol

\ua9 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.Introduction Parkinson\u27s disease (PD) is the second most common neurological disease globally, for which currently no one definitive cause or cure exists. Estimates suggest that 145 000 people with Parkinson\u27s (PwP) live in the UK. PD presents with motor and non-motor symptoms fluctuating significantly in and between individuals continually throughout the day. PD adversely affects activities of daily living, quality of life and well-being. Self-efficacy is an important belief to improve for PwP as it enables the individual to develop confidence in their ability to exert control over their own motivation, behaviour and social environment. This scoping review aims to identify digital technologies which have been shown to positively impact on promoting self-efficacy in PwP. Methods and analyses Six bibliographic databases MEDLINE, PsycINFO, Web of Science, CINAHL, EMBASE and IEEE Xplore will be searched from the date of their inception to the May 2023. The primary outcome will be to identify interventions which are associated with a change in self-efficacy in PwP to enable positive and negative outcomes, as well as safety to be evaluated. The secondary outcomes of this review will focus on the intervention\u27s proposed mechanisms for success, particularly looking at the impact they had on positive behaviour change(s) or modification(s) on study participants. Ethics and dissemination This scoping review will not require ethical approval as it will use data collected from previously published primary studies. The findings of this review will be published in peer-reviewed journals and widely disseminated

Quantifying drug-induced dyskinesias in the arms using digitised spiral-drawing tasks.

In this study, we quantify the severity of drug-induced dyskinesias in the arms of Parkinson's disease (PD) patients using digitised spiral-drawing tasks. Two spiral drawings, namely a circular and a square spiral, are designed to, respectively, represent the continuous and discrete arm motions, and the size of the spiral is decided so that both the distal and proximal arm joints are involved. Fifteen PD patients, average disease duration 14.4+/-7.4 years, were assessed 30 min after a levodopa challenge whilst performing circular and square spiral-drawing tasks. The velocity of drawing movements was computed and the amplitude of the involuntary dyskinetic movements was measured as the standard deviation of the drawing velocity (SD-DV). The mean amplitude of dyskinetic movements was compared between arms and tasks and was correlated with clinical measures including the Bain dyskinesia scale and the total unified Parkinson's disease rating scale (UPDRS) score. The results showed that there was no statistically significant difference in the amplitude of dyskinesias either between the arms or between the continuous (circular) and discrete (square) spiral drawings in this group of PD patients, but interestingly the interaction between arm and drawing pattern was significant. Significant correlations were found between the magnitude of dyskinesia measured from the spiral-drawing tasks and both the 'on' or 'off' UPDRS and also the Bain dyskinesia scale. We conclude that the drawing tasks may be used to provide an objective method of quantifying the severity of drug-induced dyskinesias in the arm in PD patients

Measurement properties of quality of life measurement instruments for infants, children and adolescents with eczema: protocol for a systematic review

Background: Eczema is a common chronic or chronically relapsing skin disease that has a substantial impact on quality of life (QoL). By means of a consensus-based process, the Harmonising Outcome Measures in Eczema (HOME) initiative has identified QoL as one of the four core outcome domains to be assessed in all eczema trials. Few measurement instruments exist to measure QoL in infants and children with eczema, but there is a great variability in both content and quality (for example, reliability and validity) of the instruments used, and it is not always clear if the best instrument is being used. Therefore, the aim of the proposed research is a comprehensive systematic assessment of the measurement properties of the existing measurement instruments that were developed and/or validated for the measurement of patient-reported QoL in infants and children with eczema. Methods/Design: This study is a systematic review of the measurement properties of patient-reported measures of QoL developed and/or validated for infants and children with eczema. Medline via PubMed and EMBASE will be searched using a selection of relevant search terms. Eligible studies will be primary empirical studies evaluating, describing, or comparing measurement properties of QoL instruments for infants and children with eczema. Eligibility assessment and data abstraction will be performed independently by two reviewers. Evidence tables will be generated for study characteristics, instrument characteristics, measurement properties, and interpretability. The adequacy of the measurement properties will be assessed using predefined criteria. Methodological quality of studies will be assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A best evidence synthesis will be undertaken if more than one study has investigated a particular measurement property. Discussion: The proposed systematic review will produce a comprehensive assessment of measurement properties of existing QoL instruments in infants and children with eczema. We aim to identify one best currently available instrument to measure QoL in infants and/or children with eczema

Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis

This project was supported through a studentship awarded by the Plymouth University Peninsula Schools of Medicine and Dentistry.Proliferator-activated receptor γ (PPARγ) activation can result in transcription of proteins involved in oxidative stress defence and mitochondrial biogenesis which could rescue mitochondrial dysfunction in Parkinson's disease (PD).The PPARγ agonist pioglitazone is protective in models of PD; however side effects have limited its clinical use. The cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) may have PPARγ dependent anti-oxidant properties. Here we investigate the effects of Δ9-THC and pioglitazone on mitochondrial biogenesis and oxidative stress. Differentiated SH-SY5Y neuroblastoma cells were exposed to the PD relevant mitochondrial complex 1 inhibitor 1-methyl- 4-phenylpyridinium iodide (MPP+). We found that only Δ9-THC was able to restore mitochondrial content in MPP+ treated SH-SY5Y cells in a PPARγ dependent manner by increasing expression of the PPARγ co-activator 1a (PGC-1a), the mitochondrial transcription factor (TFAM) as well as mitochondrial DNA content. Co-application of Δ9- THC with pioglitazone further increased the neuroprotection against MPP+ toxicity as compared to pioglitazone treatment alone. Furthermore, using lentiviral knock down of the PPARγ receptor we showed that, unlike pioglitazone, Δ9-THC resulted in a PPARγ dependent reduction of MPP+ induced oxidative stress. We therefore suggest that, in contrast to pioglitazone, Δ9-THC mediates neuroprotection via PPARγ-dependent restoration of mitochondrial content which may be beneficial for PD treatment.Publisher PDFPeer reviewe