A durable gain in motor and non-motor symptoms of Parkinson’s Disease following repeated caloric vestibular stimulation: A single-case study

Objective: To gain ‘first-in-man’ evidence that repeated caloric vestibular stimulation (CVS), a non-invasive form of neuro-modulation, can induce a lasting and clinically-relevant reduction in Parkinson’s Disease (PD) symptoms. Methods: A 70yr old male, diagnosed with PD 7 years prior to study enrolment, self-administered CVS at home 2x20 minutes per day for three months using a solid-state portable device. Standardised neuropsychological assessments of motor, cognitive, affective and independent function were carried out prior to stimulation, at the start and end of the sham (month 1) and active (months 2-3) phases, and 5 months post-stimulation. Results: Relative to the pre-stimulation baseline, behavioural improvements that exceeded the minimal detectable change were observed on the EQ5D, Unified Parkinson’s Disease Rating Scale, Schwab and England scale, 2 minute walk, Timed up and go, Non-motor symptom assessment scale for PD, Montreal cognitive assessment, Hospital depression scale and Epworth sleepiness scale. The level of change exceeded the threshold for a minimal clinically important difference on all scales for which a threshold has been published. By contrast, little improvement was seen during the sham (i.e. placebo) phase. Conclusion: Caloric vestibular stimulation may offer a novel, home-based method of relieving everyday symptoms of PD, and merits further evaluative study

Unlocking the potential of higher-molecular-weight 5-HT7R ligands. Synthesis, affinity, and ADMET examination

An increasing number of drugs introduced to the market and numerous repositories of compounds with confirmed activity have posed the need to revalidate the state-of-the-art rules that determine the ranges of properties the compounds should possess to become future drugs. In this study, we designed a series of two chemotypes of aryl-piperazine hydantoin ligands of 5-HT7R, an attractive target in search for innovative CNS drugs, with higher molecular weight (close to or over 500). Consequently, 14 new compounds were synthesised and screened for their receptor activity accompanied by extensive docking studies to evaluate the observed structure–activity/properties relationships. The ADMET characterisation in terms of the biological membrane permeability, metabolic stability, hepatotoxicity, cardiotoxicity, and protein plasma binding of the obtained compounds was carried out in vitro. The outcome of these studies constituted the basis for the comprehensive challenge of computational tools for ADMET properties prediction. All the compounds possessed high affinity to the 5-HT7R (Ki below 250 nM for all analysed structures) with good selectivity over 5-HT6R and varying affinity towards 5-HT2AR, 5-HT1AR and D2R. For the best compounds of this study, the expression profile of genes associated with neurodegeneration, anti-oxidant response and anti-inflammatory function was determined, and the survival of the cells (SH-SY5Y as an in vitro model of Alzheimer’s disease) was evaluated. One 5-HT7R agent (32) was characterised by a very promising ADMET profile, i.e. good membrane permeability, low hepatotoxicity and cardiotoxicity, and high metabolic stability with the simultaneous high rate of plasma protein binding and high selectivity over other GPCRs considered, together with satisfying gene expression profile modulations and neural cell survival. Such encouraging properties make it a good candidate for further testing and optimisation as a potential agent in the treatment of CNS-related disorders

Exploring hyperhidrosis and related thermoregulatory symptoms as a possible clinical identifier for the dysautonomic subtype of Parkinson’s disease

ObjectiveTo identify associated (non-)motor profiles of Parkinson’s disease (PD) patients with hyperhidrosis as a dominant problem.MethodsThis is a cross-sectional, exploratory, analysis of participants enrolled in the Non-motor Longitudinal International Study (NILS; UKCRN No: 10084) at the Parkinson’s Centre at King’s College Hospital (London, UK). Hyperhidrosis scores (yes/no) on question 28 of the Non-Motor Symptom Questionnaire were used to classify patients with normal sweat function (n = 172) and excessive sweating (n = 56) (Analysis 1; n = 228). NMS scale (NMSS) question 30 scores were used to stratify participants based on hyperhidrosis severity (Analysis 2; n = 352) using an arbitrary severity grading: absent score 0 (n = 267), mild 1–4 (n = 49), moderate 5–8 (n = 17), and severe 9–12 (n = 19). NMS burden, as well as PD sleep scale (PDSS) scores were then analysed along with other correlates.ResultsNo differences were observed in baseline demographics between groups in either analysis. Patients with hyperhidrosis exhibited significantly higher total NMSS burden compared to those without (p p p ConclusionsChronic hyperhidrosis appears to be associated with a dysautonomia dominant subtype in PD patients, which is also associated with sleep disorders and a higher rate of dyskinesia (fluctuation-related hyperhidrosis). These data should prompt the concept of hyperhidrosis being used as a simple clinical screening tool to identify PD patients with autonomic symptoms.</div

Caloric vestibular stimulation for the management of motor and non-motor symptoms in Parkinson's disease

Introduction: A recent case study showed that repeated sessions of caloric vestibular stimulation (CVS) relieved motor and non-motor symptoms associated with Parkinson's disease (PD). Here we sought to confirm these results in a prospective, double-blind, randomized, placebo treatment-controlled study. Methods: 33 PD subjects receiving stable anti-Parkinsonian therapy completed an active (n = 16) or placebo (n = 17) treatment period. Subjects self-administered CVS at home twice-daily via a portable, pre-programmed, solid-state ThermoNeuroModulation (TNMTM) device, which delivered continually-varying thermal waveforms through aluminum ear-probes mounted on a wearable headset. Subjects were followed over a 4-week baseline period, 8 weeks of treatment and then at 5- and 24-weeks post-treatment. At each study visit, standardized clinical assessments were conducted during ON-medication states to evaluate changes in motor and non-motor symptoms, activities of daily living, and quality of life ratings. Results: Change scores between baseline and the end of treatment showed that active-arm subjects demonstrated clinically-relevant reductions in motor and non-motor symptoms that were significantly greater than placebo- arm subjects. Active treatment was also associated with improved scores on activities of daily living assessments. Therapeutic gains were still evident 5 weeks after the end of active treatment but had started to recede at 24 weeks follow-up. No serious adverse events were associated with device use, and there was high participant satisfaction and tolerability of treatment. Conclusion: The results provide evidence that repeated CVS can provide safe and enduring adjuvant relief for motor and non-motor symptoms associated with PD

Study Protocol: Randomised Controlled Hybrid Type 2 Trial Evaluating the Scale-up of Two Arts Interventions for Postnatal Depression and Parkinson’s Disease

INTRODUCTION: Research on the benefits of \u27arts\u27 interventions to improve individuals\u27 physical, social and psychological well-being is growing, but evidence on implementation and scale-up into health and social care systems is lacking. This protocol reports the SHAPER-Implement programme (Scale-up of Health-Arts Programmes Effectiveness-Implementation Research), aimed at studying the impact, implementation and scale-up of: Melodies for Mums (M4M), a singing intervention for postnatal depression; and Dance for Parkinson\u27s (PD-Ballet) a dance intervention for Parkinson\u27s disease. We examine how they could be embedded in clinical pathways to ensure their longer-term sustainability. METHODS AND ANALYSIS: A randomised two-arm effectiveness-implementation hybrid type 2 trial design will be used across M4M/PD-Ballet. We will assess the implementation in both study arms (intervention vs control), and the cost-effectiveness of implementation. The design and measures, informed by literature and previous research by the study team, were refined through stakeholder engagement. Participants (400 in M4M; 160 in PD-Ballet) will be recruited to the intervention or control group (2:1 ratio). Further implementation data will be collected from stakeholders involved in referring to, delivering or supporting M4M/PD-Ballet (N=25-30 for each intervention).A mixed-methods approach (surveys and semi-structured interviews) will be employed. \u27Acceptability\u27 (measured by the \u27Acceptability Intervention Measure\u27) is the primary implementation endpoint for M4M/PD-Ballet. Relationships between clinical and implementation outcomes, implementation strategies (eg, training) and outcomes will be explored using generalised linear mixed models. Qualitative data will assess factors affecting the acceptability, feasibility and appropriateness of M4M/PD-Ballet, implementation strategies and longer-term sustainability. Costs associated with implementation and future scale-up will be estimated. ETHICS AND DISSEMINATION: SHAPER-PND (the M4M trial) and SHAPER-PD (the PD trial) are approved by the West London and GTAC (20/PR/0813) and the HRA and Health and Care Research Wales (REC Reference: 20/WA/0261) Research Ethics Committees. Study findings will be disseminated through scientific peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBERS: Both trials are registered with NIH US National Library of Medicine, ClinicalTrials.gov. The trial registration numbers, URLs of registry records, and dates of registration are: (1) PD-Ballet: URL: NCT04719468 (https://eur03.safelinks.protection. OUTLOOK: com/?url=https%3A%2F%2Fwww.clinicaltrials.gov%2Fct2%2Fshow%2FNCT04719468%3Fterm%3DNCT04719468%26draw%3D2%26rank%3D1&data=04%7C01%7Crachel.davis%40kcl.ac.uk%7C11a7c5142782437919f808d903111449%7C8370cf1416f34c16b83c724071654356%7C0%7C0%7C6375441942616) (date of registration: 22 Jan 2021). (2) Melodies for Mums: NCT04834622 (https://clinicaltrials.gov/ct2/show/NCT04834622?term=shaper-pnd&draw=2&rank=1) (date of registration: 8 Apr 2021)

Scaling-up Health-Arts Programmes : the largest study in the world bringing arts-based mental health interventions into a national health service

The Scaling-up Health-Arts Programme: Implementation and Effectiveness Research (SHAPER) project is the world's largest hybrid study on the impact of the arts on mental health embedded into a national healthcare system. This programme, funded by the Wellcome Trust, aims to study the impact and the scalability of the arts as an intervention for mental health. The programme will be delivered by a team of clinicians, research scientists, charities, artists, patients and healthcare professionals in the UK's National Health Service (NHS) and the community, spanning academia, the NHS and the charity sector. SHAPER consists of three studies - Melodies for Mums, Dance for Parkinson's, and Stroke Odysseys - which will recruit over 800 participants, deliver the interventions and draw conclusions on their clinical impact, implementation effectiveness and cost-effectiveness. We hope that this work will inspire organisations and commissioners in the NHS and around the world to expand the remit of social prescribing to include evidence-based arts interventions

Effects of a four-strain probiotic on gut microbiota, inflammation, and symptoms in Parkinson's disease: A randomized clinical trial

Background: Gut dysbiosis and gut-brain-axis involvement in people with Parkinson's disease (PwP) support the use of gut-microbiota-modulating interventions. Probiotics may help manage constipation in PwP; however, mechanisms underpinning additional beneficial properties are unknown.   Objective: The aim was evaluating the effects of a probiotic (Lacticaseibacillus rhamnosus, Lactobacillus acidophilus, Lactiplantibacillus plantarum and Enterococcus faecium) on gut microbiota, inflammation, motor and non-motor symptoms (NMS) in PwP and constipation.   Methods: In this multicenter, randomized, double-blind, placebo-controlled trial (NCT05146921), PwP and constipation were randomized (1:1) to receive either the probiotic (4.08 × 108 CFU/mL) or placebo orally (70 mL/day) for 12 weeks. The primary endpoint was the differential abundance of gut microbiota taxa between baseline and end-of-treatment in the active versus placebo group. Secondary/exploratory endpoints included changes in inflammatory cytokines plasma levels, short-chain fatty acids (SCFAs) plasma and fecal levels, motor and NMS outcomes after 12 weeks. A per-protocol analysis was performed.   Results: Between July 17, 2019 and February 6, 2022, 74 participants were randomized. Data from 35 (probiotic) and 33 (placebo) participants were analyzed. Enrichments of bacteria with beneficial health-related properties (Odoribacteraceae, Enterococcaceae, and Blautia faecicola) were observed in the active group compared to placebo (P ≤ 0.05). Proinflammatory cytokine TNF-α plasma levels decreased with probiotic treatment and increased with placebo (P < 0.05). No changes in SCFAs levels were observed. Reductions in time-to-on and NMS scale scores (P < 0.05) were observed only in the active group.   Conclusions: This probiotic was effective in beneficially enriching the gut microbiota with potential to reduce systemic inflammation, shortening time-to-on following levodopa administration, and alleviating NMS burden in PwP experiencing constipation

Stanisławski/Osterwa: meetings and contradictions. An attempt to compare a theatrical teamwork.

Celem niniejszej pracy jest próba porównania działalności Teatru Reduta i Moskiewskiego Teatru Artystycznego, ze szczególnym uwzględnieniem ich metod pracy z aktorem. Pierwszy rozdział przybliża początki teatru założonego przez Konstantego Stanisławskiego, zawiera jego najważniejsze postulaty dotyczące etyki aktorskiej oraz główne elementy stworzonego przez niego „systemu”. Dodatkowo opisuje powstanie Pierwszego Studia MChT, gdzie Stanisławski rozwija laboratoryjny charakter pracy. Drugi rozdział przedstawia okoliczności spotkania twórców polskich z rosyjskim reformatorem, opisuje powstanie Teatru Reduta i pierwszy okres jego działalności. Trzeci rozdział ukazuje inspiracje Reduty Moskiewskim Teatrem Artystycznym, poprzez przedstawienie elementów pokrewnych w pracy Reduty.The aim of this paper is a comparison between an experimental theatre Reduta and The Moscow Art Theatre (abbreviated to MChT), with a focus on their methods of working with actors. The first chapter presents the beginnings of a theatre established by Konstanty Stanisławski. It describes Stanisławski’s most important proposals pertaining to an actor’s work ethic, and the system which he created. Additionally, the chapter describes the establishment of the First Studio of the Moscow Art Theatre, where Stanisławski developed his laboratory-like way of work. The second chapter introduces the circumstances surrounding the meeting of Polish authors with a Russian reformer, and describes the creation of Reduta and its very beginnings. The third chapter presents Reduta’s inspirations with MChT by presenting certain aspects of Reduta’s work that are akin to MChT

Analysis of translations of idiomatic expressions with the lexeme ki from selected works by Akutagawa Ryūnosuke

Celem niniejszej pracy jest przeanalizowanie tłumaczeń wyrażeń idiomatycznych zawierających leksem ki z języka japońskiego na język polski występujących w czterech wybranych utworach Akutagawy Ryūnosuke. Praca składa się z trzech rozdziałów. Pierwszy z nich przedstawia wybrane zagadnienia z teorii przekładu. W kolejnym rozdziale przybliżone zostaną najważniejsze pojęcia z zakresu frazeologii polskiej oraz japońskiej, a także przedstawiony zostanie leksem ki. W ostatnim rozdziale zostanie zawarta analiza wariantów tłumaczeniowych wyrażeń z leksemem ki występujących w opowiadaniach Akutagawy Ryūnosuke, w oparciu o podstawy teoretyczne przedstawione w rozdziale pierwszym i drugim. Analizie poddane zostanie łącznie osiemnaście fragmentów opowiadań, umieszczonych w kontekstach fabularnych.The purpose of this paper is to analyze the translations of idiomatic expressions with the lexeme ki from Japanese into Polish in four selected works by Akutagawa Ryūnosuke. The paper consists of three chapters. The first one presents selected issues in translation theory. The next chapter will introduce the most important concepts of Polish and Japanese phraseology and introduce the lexeme ki. The last chapter will include an analysis of the translation variants of expressions with the lexeme ki in Akutagawa Ryūnosuke's short stories, based on the theoretical foundations presented in first two chapters. A total of eighteen short story excerpts will be analyzed, placed in story contexts