Progression of Neuropsychiatric Symptoms over Time in an Incident Parkinson's Disease Cohort (ICICLE-PD).

BACKGROUND: Cross-sectional studies have identified that the prevalence of neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) ranges from 70-89%. However, there are few longitudinal studies determining the impact of NPS on quality of life (QoL) in PD patients and their caregivers. We seek to determine the progression of NPS in early PD. METHODS: Newly diagnosed idiopathic PD cases (n = 212) and age-matched controls (n = 99) were recruited into a longitudinal study. NPS were assessed using the Neuropsychiatric Inventory with Caregiver Distress scale (NPI-D). Further neuropsychological and clinical assessments were completed by participants, with reassessment at 18 and 36 months. Linear mixed-effects modelling determined factors associated with NPI-D and QoL over 36 months. RESULTS: Depression, anxiety, apathy and hallucinations were more frequent in PD than controls at all time points (p < 0.05). Higher motor severity at baseline was associated with worsening NPI-D scores over time (β = 0.1, p < 0.05), but not cognition. A higher NPI total score was associated with poorer QoL at any time point (β = 0.3, p < 0.001), but not changed in QoL scores. CONCLUSION: NPS are significantly associated with poorer QoL, even in early PD. Screening for NPS from diagnosis may allow efficient delivery of better support and treatment to patients and their families

Cognitive impairment in Parkinson's disease: impact on quality of life of carers.

BACKGROUND: The quality of life (QoL) of informal caregivers of people with Parkinson's disease (PD) (PwP) can be affected by the caring role. Because of cognitive symptoms and diminished activities of daily living, in addition to the management of motor symptoms, carers of PwP and cognitive impairment may experience increased levels of burden and poorer QoL compared with carers of PwP without cognitive impairment. This study aimed to investigate the impact of cognitive impairment in PD upon QoL of carers. METHODS: Approximately 36 months after diagnosis, 66 dyadic couples of PwP and carers completed assessments. PwP completed a schedule of neuropsychological assessments and QoL measures; carers of PwP completed demographic questionnaires and assessments of QoL. Factor scores of attention, memory/executive function and global cognition, as derived by principal component analysis, were used to evaluate cognitive domains. RESULTS: Hierarchical regression analysis found lower Montreal Cognitive Assessment was a significant independent predictor of poorer carer QoL, in addition to number of hours spent caregiving, carer depression and PD motor severity. Attentional deficits accounted for the largest proportion of variance of carer QoL. Carers of PwP and dementia (n = 9) had significantly poorer QoL scores compared with PwP and mild cognitive impairment (n = 18) or normal cognition (n = 39) carers (p < 0.01). CONCLUSIONS: Attentional deficits were the strongest predictor of carer QoL compared with other cognitive predictors. Carers for those with PD dementia reported the poorest QoL. Interventions such as respite or cognitive behavioural therapy to improve mood and self-efficacy in carers may improve carer QoL. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd

Path Size Logit route choice models: Issues with current models, a new internally consistent approach, and parameter estimation on a large-scale network with GPS data

Path Size Logit route choice models attempt to capture the correlation between routes by including correction terms within the route utility functions. This provides a convenient closed-form solution for implementation in traffic network models. The path size terms measure distinctiveness of routes; a route is penalised based on the number of other routes sharing its links, and the costs of those shared links. Typically, real road networks have many very long routes that should be considered unrealistic. Such unrealistic routes are problematic for the Path Size Logit (PSL) model because they negatively impact the choice probabilities of realistic routes when links are shared. The Generalised Path Size Logit (GPSL) model attempts to address this problem by weighting the contributions of routes to path size terms according to the ratio of route travel costs. However, the GPSL model is not internally consistent in how it defines routes as being unrealistic: the path size terms consider only travel cost, whereas the route choice probability relation considers disutility including the correction term. To solve these challenges, this paper formulates a new internally consistent Adaptive Path Size Logit (APSL) model wherein routes contribute to path size terms according to the ratio of route choice probabilities, ensuring that routes defined as unrealistic by the path size terms, are exactly those with very low choice probabilities. The APSL route choice probability relation is an implicit function, naturally expressed as a fixed-point problem. A proof is provided for the guaranteed existence of solutions, as well as conditions for the uniqueness of solutions. A Maximum Likelihood Estimation procedure is given for estimating the APSL model with tracked route observation data, and this procedure is investigated in a simulation study where it is shown it is generally possible to reproduce assumed true parameters. APSL is then estimated using real tracked route GPS data on a large-scale network, and results are compared with other PSL models

A systematic review investigating fatigue, psychological and cognitive impairment following TIA and minor stroke:protocol paper

Approximately 20,000 people have a transient ischemic attack (TIA) and 23,375 have a minor stroke in England each year. Fatigue, psychological and cognitive impairments are well documented post-stroke. Evidence suggests that TIA and minor stroke patients also experience these impairments; however, they are not routinely offered relevant treatment. This systematic review aims to: (1) establish the prevalence of fatigue, anxiety, depression, post-traumatic stress disorder (PTSD) and cognitive impairment following TIA and minor stroke and to investigate the temporal course of these impairments; (2) explore impact on quality of life (QoL), change in emotions and return to work; (3) identify where further research is required and to potentially inform an intervention study

Cerebral glucose metabolism and cognition in newly diagnosed Parkinson’s disease: ICICLE-PD study

This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1136/jnnp-2016-31391

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Personalized online information search and visualization

BACKGROUND: The rapid growth of online publications such as the Medline and other sources raises the questions how to get the relevant information efficiently. It is important, for a bench scientist, e.g., to monitor related publications constantly. It is also important, for a clinician, e.g., to access the patient records anywhere and anytime. Although time-consuming, this kind of searching procedure is usually similar and simple. Likely, it involves a search engine and a visualization interface. Different words or combination reflects different research topics. The objective of this study is to automate this tedious procedure by recording those words/terms in a database and online sources, and use the information for an automated search and retrieval. The retrieved information will be available anytime and anywhere through a secure web server. RESULTS: We developed such a database that stored searching terms, journals and et al., and implement a piece of software for searching the medical subject heading-indexed sources such as the Medline and other online sources automatically. The returned information were stored locally, as is, on a server and visible through a Web-based interface. The search was performed daily or otherwise scheduled and the users logon to the website anytime without typing any words. The system has potentials to retrieve similarly from non-medical subject heading-indexed literature or a privileged information source such as a clinical information system. The issues such as security, presentation and visualization of the retrieved information were thus addressed. One of the presentation issues such as wireless access was also experimented. A user survey showed that the personalized online searches saved time and increased and relevancy. Handheld devices could also be used to access the stored information but less satisfactory. CONCLUSION: The Web-searching software or similar system has potential to be an efficient tool for both bench scientists and clinicians for their daily information needs

Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease

We investigated whole-brain atrophy and ventricular enlargement over 18 months in nondemented Parkinson's disease (PD) and examined their associations with clinical measures and baseline CSF markers. PD subjects (n = 100) were classified at baseline into those with mild cognitive impairment (MCI; PD-MCI, n = 36) and no cognitive impairment (PD-NC, n = 64). Percentage of whole-brain volume change (PBVC) and ventricular expansion over 18 months were assessed with FSL-SIENA and ventricular enlargement (VIENA) respectively. PD-MCI showed increased global atrophy (-1.1% ± 0.8%) and ventricular enlargement (6.9 % ± 5.2%) compared with both PD-NC (PBVC: -0.4 ± 0.5, p < 0.01; VIENA: 2.1% ± 4.3%, p < 0.01) and healthy controls. In a subset of 35 PD subjects, CSF levels of tau, and Aβ42/Aβ40 ratio were correlated with PBVC and ventricular enlargement respectively. The sample size required to demonstrate a 20% reduction in PBVC and VIENA was approximately 1/15th of that required to detect equivalent changes in cognitive decline. These findings suggest that longitudinal MRI measurements have potential to serve as surrogate markers to complement clinical assessments for future disease-modifying trials in PD.This study was funded by a Parkinson's UK grant (J-0802) and supported by Parkinson's UK (CN), Lockhart Parkinson's Disease Research Fund (RAL, TKK, GWD), Michael J. Fox Foundation (AJY), the National Institute for Health Research (NIHR, RG64473) Cambridge Biomedical Research Centre, and Biomedical Research Unit in Dementia, the Wellcome Trust (JBR, 103838); the Medical Research Council of Cognition, and Brain Sciences Unit, Cambridge (JBR, MC-A060-5PQ30); the NIHR Newcastle Biomedical Research Unit based at Newcastle-upon-Tyne Hospitals NHS Foundation Trust and Newcastle University; the NIHR Dementia and Neurodegenerative Diseases Research Network (JTO), and Elijah Mak was in receipt of the Gates Cambridge studentship and Alzheimer's Research UK scholarship

Restoration of diaphragmatic function after diaphragm reinnervation by inferior laryngeal nerve; experimental study in rabbits

OBJECTIVES: To assess the possibilities of reinnervation in a paralyzed hemidiaphragm via an anastomosis between phrenic nerve and inferior laryngeal nerve in rabbits. Reinnervation of a paralyzed diaphragm could be an alternative to treat patients with ventilatory insufficiency due to upper cervical spine injuries. MATERIAL AND METHOD: Rabbits were divided into five groups of seven rabbits each. Groups I and II were respectively the healthy and the denervated control groups. The 3 other groups were all reinnervated using three different surgical procedures. In groups III and IV, phrenic nerve was respectively anastomosed with the abductor branch of the inferior laryngeal nerve and with the trunk of the inferior laryngeal nerve. In group V, the fifth and fourth cervical roots were respectively anastomosed with the abductor branch of the inferior laryngeal nerve and with the nerve of the sternothyroid muscle (originating from the hypoglossal nerve). Animals were evaluated 4 months later using electromyography, transdiaphragmatic pressure measurements, sonomicrometry and histological examination. RESULTS: A poor inspiratory activity was found in quiet breathing in the reinnervated groups, with an increasing pattern of activity during effort. In the reinnervated groups, transdiaphragmatic pressure measurements and sonomicrometry were higher in group III with no significant differencewith groups IV and V. CONCLUSION: Inspiratory contractility of an hemidiaphragm could be restored with immediate anastomosis after phrenic nerve section between phrenic nerve and inferior laryngeal nerve

Comparison of the efficacy of a neutral wrist splint and wrist splint with lumbrical unit for the treatment of patients with carpal tunnel syndrome

Purpose: The purpose of this study was to compare the effect of a neutral wrist splint or a wrist splint with an additional metacarpophalangeal (MCP) unit on pain, function, grip and pinch strength in patients with mild-to-moderate carpal tunnel syndrome (CTS). Methods: Twenty four patients received conservative treatment using either the neutral wrist splint or wrist splint with the MCP unit for a period of 6 weeks. Primary outcome measures were pain, function, grip and pinch strength. Data was collected immediately before and after using the two types of splints at baseline (0 weeks) and 6 weeks. Statistical analysis was performed using the paired t-test and independent T-test. Results: Compared to baseline, both the neutral wrist splint and the wrist splint with an MCP unit significantly decreased pain, increased function and pinch and grip strength. Comparisons of the two types of splints for grip (P =0.675) and pinch strength (P =0.650) revealed that there were no significant differences between the two after 6 weeks of wear. However, there were significant differences in pain levels (P =0.022) and the DASH score (P =0.027) between the two types of splints from baseline to 6 weeks. Conclusion: The wrist splint with an MCP unit was more effective than the neutral wrist splint in pain reduction and improvement of function