A systematic review of biomarkers for disease progression in Parkinson's disease

This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0707-10124).BACKGROUND: Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson's disease (PD) exist. METHODS: MEDLINE and EMBASE (1950-2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came. RESULTS: 183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality--cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses. CONCLUSION: We found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional 'roadmap' for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged.Publisher PDFPeer reviewe

Standing up in Multiple Sclerosis (SUMS): Protocol for a multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of a home-based self-management standing frame programme in people with progressive multiple sclerosis.

This study is funded by the NIHR Health Technology Assessment Programme (14/176/12), United Kingdom.Background:  Impaired mobility is a cardinal feature of multiple sclerosis (MS) and is rated by people with MS as their highest priority. By the secondary progressive phase, balance, mobility and physical activity levels are significantly compromised; an estimated 70% of people with secondary progressive MS fall regularly. Our ongoing research has systematically developed ‘Balance Right in MS’ (BRiMS), an innovative, manualised 13-week guided self-management programme tailored to the needs of people with MS, designed to improve safe mobility and minimise falls. Our eventual aim is to assess the clinical and cost effectiveness of BRiMS in people with secondary progressive MS by undertaking an appropriately statistically powered, multi-centre, assessor-blinded definitive, randomised controlled trial. This feasibility study will assess the acceptability of the intervention and test the achievability of running such a definitive trial. Methods/design:  This is a pragmatic multi-centre feasibility randomised controlled trial with blinded outcome assessment. Sixty ambulant people with secondary progressive MS who self-report two or more falls in the previous 6 months will be randomly allocated (1:1) to either the BRiMS programme plus usual care or to usual care alone. All participants will be assessed at baseline and followed up at 15 weeks and 27 weeks post-randomisation. The outcomes of this feasibility trial include: • Feasibility outcomes, including trial recruitment, retention and completion • Assessment of the proposed outcome measures for the anticipated definitive trial (including measures of walking, quality of life, falls, balance and activity level) • Measures of adherence to the BRiMS programme • Data to inform the economic evaluation in a future trial • Process evaluation (assessment of treatment fidelity and qualitative evaluation of participant and treating therapist experience) Discussion:  The BRiMS intervention aims to address a key concern for MS service users and providers. However, there are several uncertainties which need to be addressed prior to progressing to a full-scale trial, including acceptability of the BRiMS intervention and practicality of the trial procedures. This feasibility trial will provide important insights to resolve these uncertainties and will enable a protocol to be finalised for use in the definitive trial.Publisher PDFPeer reviewe

Anomalous high-magnetic field electronic state of the nematic superconductors FeSe₁₋ₓSₓ

Understanding superconductivity requires detailed knowledge of the normal electronic state from which it emerges. A nematic electronic state that breaks the rotational symmetry of the lattice can potentially promote unique scattering relevant for superconductivity. Here, we investigate the normal transport of superconducting FeSe1−xSx across a nematic phase transition using high-magnetic fields up to 69 T to establish the temperature and field dependencies. We find that the nematic state is dominated by a linear resistivity at low temperatures that evolves towards Fermi-liquid behavior, depending on the composition x and the impurity level. Near the nematic end point, we find an extended temperature regime with ∼T1.5 resistivity, different from the behavior found near an antiferromagnetic critical point. The variation of the resistivity exponent with temperature reflects the importance of the nematoelastic coupling that can also suppress divergent critical fluctuations at the nematic end point. The transverse magnetoresistance inside the nematic phase has a ∼H1.55 dependence over a large magnetic field range and it displays an unusual peak at low temperatures inside the nematic phase. Our study reveals anomalous transport inside the nematic phase, influenced by both changes in the electronic structure and the scattering with the lattice and spin fluctuations

Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review

<p>Abstract</p> <p>Background</p> <p>Cannabis therapy has been considered an effective treatment for spasticity, although clinical reports of symptom reduction in multiple sclerosis (MS) describe mixed outcomes. Recently introduced therapies of combined Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) extracts have potential for symptom relief with the possibility of reducing intoxication and other side effects. Although several past reviews have suggested that cannabinoid therapy provides a therapeutic benefit for symptoms of MS, none have presented a methodical investigation of newer cannabinoid treatments in MS-related spasticity. The purpose of the present review was to systematically evaluate the effectiveness of combined THC and CBD extracts on MS-related spasticity in order to increase understanding of the treatment's potential effectiveness, safety and limitations.</p> <p>Methods</p> <p>We reviewed MEDLINE/PubMed, Ovid, and CENTRAL electronic databases for relevant studies using randomized controlled trials. Studies were included only if a combination of THC and CBD extracts was used, and if pre- and post-treatment assessments of spasticity were reported.</p> <p>Results</p> <p>Six studies were systematically reviewed for treatment dosage and duration, objective and subjective measures of spasticity, and reports of adverse events. Although there was variation in the outcome measures reported in these studies, a trend of reduced spasticity in treated patients was noted. Adverse events were reported in each study, however combined TCH and CBD extracts were generally considered to be well-tolerated.</p> <p>Conclusion</p> <p>We found evidence that combined THC and CBD extracts may provide therapeutic benefit for MS spasticity symptoms. Although some objective measures of spasticity noted improvement trends, there were no changes found to be significant in post-treatment assessments. However, subjective assessment of symptom relief did often show significant improvement post-treatment. Differences in assessment measures, reports of adverse events, and dosage levels are discussed.</p

Антологія розвитку сімейної медицини в Дніпропетровській області за 20 років

BACKGROUND: The long-term treatment of Parkinson disease (PD) may be complicated by the development of levodopa-induced dyskinesia. Clinical and animal model data support the view that modulation of cannabinoid function may exert an antidyskinetic effect. The authors conducted a randomized, double-blind, placebo-controlled crossover trial to examine the hypothesis that cannabis may have a beneficial effect on dyskinesia in PD.METHODS: A 4-week dose escalation study was performed to assess the safety and tolerability of cannabis in six PD patients with levodopa-induced dyskinesia. Then a randomized placebo-controlled crossover study (RCT) was performed, in which 19 PD patients were randomized to receive oral cannabis extract followed by placebo or vice versa. Each treatment phase lasted for 4 weeks with an intervening 2-week washout phase. The primary outcome measure was a change in Unified Parkinson's Disease Rating Scale (UPDRS) (items 32 to 34) dyskinesia score. Secondary outcome measures included the Rush scale, Bain scale, tablet arm drawing task, and total UPDRS score following a levodopa challenge, as well as patient-completed measures of a dyskinesia activities of daily living (ADL) scale, the PDQ-39, on-off diaries, and a range of category rating scales.RESULTS: Seventeen patients completed the RCT. Cannabis was well tolerated, and had no pro- or antiparkinsonian action. There was no evidence for a treatment effect on levodopa-induced dyskinesia as assessed by the UPDRS, or any of the secondary outcome measures.CONCLUSIONS: Orally administered cannabis extract resulted in no objective or subjective improvement in dyskinesias or parkinsonism.</p

Regularity of a kind of marginal functions in Hilbert spaces

We study well-posedness of some mathematical programming problem depending on a parameter that generalizes in a certain sense the metric projection onto a closed nonconvex set. We are interested in regularity of the set of minimizers as well as of the value function, which can be seen, on one hand, as the viscosity solution to a Hamilton-Jacobi equation, while, on the other, as the minimal time in some related optimal time control problem. The regularity includes both the Fréchet differentiability of the value function and the Hölder continuity of its (Fréchet) gradient

Oral medicine acceptance in infants and toddlers: measurement properties of the caregiver-administered Children’s acceptance tool (CareCAT)

BACKGROUND: Developing age-appropriate medications remains a challenge in particular for the population of infants and toddlers, as they are not able to reliably self-report if they would accept and consequently take an oral medicine. Therefore, it is common to use caregivers as proxies when assessing medicine acceptance. The outcome measures used in this research field differ and most importantly lack validation, implying a persisting gap in knowledge and controversy in the field. The newly developed Caregiver-administered Children’s Acceptance Tool (CareCAT) is based on a 5-point nominal scale, with descriptors of medication acceptance behavior. This crosssectional study assessed the measurement properties of the tool with regards to the user’s understanding and its intra- and inter-rater reliability. METHODS: Participating caregivers were enrolled at a primary healthcare facility where their children (median age 6 months) had been prescribed oral antibiotics. Caregivers, trained observers and the tool developer observed and scored on the CareCAT tool what behavior children exhibited when receiving the medicine (n = 104). The videorecords of this process served as replicate observations (n = 69). After using the tool caregivers were asked to explain their observations and the tool descriptors in their own words. The tool’s reliability was assessed by percentage agreement and Cohen’s unweighted kappa coefficients of agreement for nominal scales. RESULTS: The study found that caregivers using CareCAT had a satisfactory understanding of the tool’s descriptors. Using its dichotomized scores the tool reliably was strong for acceptance behavior (agreement inter-rater 84–88%, kappa 0.66–0.76; intra-rater 87–89%, kappa 0.68–0.72) and completeness of medicine ingestion (agreement inter-rater 82–86%, kappa 0.59–0.67; intra-rater 85–93%, kappa 0.50–0.70). CONCLUSIONS: The CareCAT is a low-cost, easy-to-use and reliable instrument, which is relevant to assess acceptance behavior and completeness of medicine ingestion, both of which are of significant importance for developing age-appropriate medications in infants and toddlers

Human-Centered Design Components in Spiral Model to Improve Mobility of Older Adults

As humans grow older, their cognitive needs change more frequently due to distal and proximal life events. Designers and developers need to come up with better designs that integrate older users’ needs in a short period of time with more interaction with the users. Therefore, the positioning of human end users in the center of the design itself is not the key to the success of design artifacts while designing applications for older adults to use a smartphone as a promising tool for journey planner while using public transportation. This study analyzed the use of human-centered design (HCD) components, the spiral model, and the design for failure (DfF) approach to improve the interactions between older users and designers/developers in gathering usability needs in the concept stage and during the development of the app with short iterative cycles. To illustrate the importance of the applied approach, a case study with particular focus on older adults is presented.The results presented in this study are based on “Assistant” project funded by AAL JP, co-funded by the European Union. The authors would like to thank Dr. Stefan Carmien, my colleague in Assistant, for mentoring and for reading and making comments in the earlier versions of this chapter; participating research institutes; funding agencies; and companies from Finland, Spain, Austria, France, and the United Kingdom for their active support throughout the project