Showing papers by "University College London published in 2008"
TL;DR: The Medical Research Council's evaluation framework (2000) brought welcome clarity to the task and now the council has updated its guidance.
Abstract: Evaluating complex interventions is complicated. The Medical Research Council9s evaluation framework (2000) brought welcome clarity to the task. Now the council has updated its guidance
8,896 citations
TL;DR: The Commission on Social Determinants of Health (CSDH) as mentioned in this paper was created to marshal the evidence on what can be done to promote health equity and to foster a global movement to achieve it.
7,335 citations
Rush University Medical Center1, Medical University of South Carolina2, Columbia University3, Innsbruck Medical University4, University of Lisbon5, University of Pennsylvania6, University of Marburg7, University of Paris8, University of Rochester9, Baylor College of Medicine10, Autonomous University of Barcelona11, University of Toronto12, University College London13, Wayne State University14, University of Illinois at Chicago15, Icahn School of Medicine at Mount Sinai16, University of Toulouse17, Leiden University18, University of Massachusetts Medical School19
TL;DR: The combined clinimetric results of this study support the validity of the MDS‐UPDRS for rating PD.
Abstract: We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.
4,589 citations
Radboud University Nijmegen1, National Institutes of Health2, Stanford University3, University of California, Los Angeles4, University of Lausanne5, University of Alabama6, University of Paris7, University of Michigan8, University of Texas Health Science Center at San Antonio9, University of Strasbourg10, University of Manchester11, University College London12, Oregon Health & Science University13, Complutense University of Madrid14, University of Aberdeen15, Duke University16, Charité17, University at Buffalo18, Wayne State University19, University of Sydney20, University of Genoa21, University of Florida22, University of Pennsylvania23
TL;DR: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
Abstract: BACKGROUND: Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies. METHODS: After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved. RESULTS: The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only. CONCLUSIONS: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.
4,389 citations
Federal University of Bahia1, McMaster University2, University of Amsterdam3, National Institutes of Health4, Charité5, Catholic University of Cordoba6, University of Genoa7, Radboud University Nijmegen8, Transilvania University of Brașov9, Ghent University10, University of Tennessee Health Science Center11, University of Naples Federico II12, Laval University13, Universidade Federal de Minas Gerais14, University of Oslo15, University of Manchester16, Aarhus University17, Imperial College London18, Erasmus University Rotterdam19, George Washington University20, Seoul National University21, Medical University of Łódź22, Hai phong University Of Medicine and Pharmacy23, Université de Montréal24, Guangzhou Medical University25, University of South Florida26, University of California, San Diego27, University of California28, University of Chicago29, Monash University30, Teikyo University31, National and Kapodistrian University of Athens32, Nippon Medical School33, Sofia Medical University34, Leiden University35, Leiden University Medical Center36, University College London37, University of Manitoba38, University of Helsinki39, Finnish Institute of Occupational Health40, National University of Singapore41, Karolinska Institutet42, University of Minnesota43, Celal Bayar University44, University of Cape Town45, Pierre-and-Marie-Curie University46, Tunis University47, University of Ghana48, University of Wisconsin-Madison49, University of British Columbia50, Georgia Regents University51, Vilnius University52, University of Washington53, University of Dundee54, University of Poitiers55, University of Mississippi56, Federal University of São Paulo57, German Red Cross58, Jagiellonian University Medical College59, Chiba University60, American Pharmacists Association61, University of Aberdeen62, University of Nevada, Reno63, University of North Carolina at Chapel Hill64
TL;DR: The ARIA guidelines for the management of allergic rhinitis and asthma are similar in both the 1999 ARIA workshop report and the 2008 Update as discussed by the authors, but the GRADE approach is not yet available.
Abstract: Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations.
In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease.
This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work.
The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available.
Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed.
The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.
3,769 citations
Mayo Clinic1, University College London2, University of California, Los Angeles3, Arizona State University4, University of California, Davis5, University of California, San Diego6, Boston University7, University of California, San Francisco8, Siemens9, General Electric10, Philips11, Johns Hopkins University12, Stanford University13, University of Virginia14
TL;DR: The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom‐based monitoring of all scanners could be used as a model for other multisite trials.
Abstract: Dementia, one of the most feared associates of increasing longevity, represents a pressing public health problem and major research priority. Alzheimer's disease (AD) is the most common form of dementia, affecting many millions around the world. There is currently no cure for AD, but large numbers of novel compounds are currently under development that have the potential to modify the course of the disease and slow its progression. There is a pressing need for imaging biomarkers to improve understanding of the disease and to assess the efficacy of these proposed treatments. Structural magnetic resonance imaging (MRI) has already been shown to be sensitive to presymptomatic disease (1-10) and has the potential to provide such a biomarker. For use in large-scale multicenter studies, however, standardized methods that produce stable results across scanners and over time are needed.
The Alzheimer's Disease Neuroimaging Initiative (ADNI) study is a longitudinal multisite observational study of elderly individuals with normal cognition, mild cognitive impairment (MCI), or AD (11,12). It is jointly funded by the National Institutes of Health (NIH) and industry via the Foundation for the NIH. The study will assess how well information (alone or in combination) obtained from MRI, (18F)-fludeoyglucose positron emission tomography (FDG PET), urine, serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical and neuropsychometric assessments, can measure disease progression in the three groups of elderly subjects mentioned above. At the 55 participating sites in North America, imaging, clinical, and biologic samples will be collected at multiple time points in 200 elderly cognitively normal, 400 MCI, and 200 AD subjects. All subjects will be scanned with 1.5 T MRI at each time point, and half of these will also be scanned with FDG PET. Subjects not assigned to the PET arm of the study will be eligible for 3 T MRI scanning. The goal is to acquire both 1.5 T and 3 T MRI studies at multiple time points in 25% of the subjects who do not undergo PET scanning [R2C1]. CSF collection at both baseline and 12 months is targeted for 50% of the subjects. Sampling varies by clinical group. Healthy elderly controls will be sampled at 0, 6, 12, 24, and 36 months. Subjects with MCI will be sampled at 0, 6, 12, 18, 24, and 36 months. AD subjects will be sampled at 0, 6, 12, and 24 months.
Major goals of the ADNI study are: to link all of these data at each time point and make this repository available to the general scientific community; to develop technical standards for imaging in longitudinal studies; to determine the optimum methods for acquiring and analyzing images; to validate imaging and biomarker data by correlating these with concurrent psychometric and clinical assessments; and to improve methods for clinical trials in MCI and AD. The ADNI study overall is divided into cores, with each core managing ADNI-related activities within its sphere of expertise: clinical, informatics, biostatistics, biomarkers, and imaging. The purpose of this report is to describe the MRI methods and decision-making process underlying the selection of the MRI protocol employed in the ADNI study.
3,611 citations
TL;DR: The OpenStreetMap project is a knowledge collective that provides user-generated street maps that follow the peer production model that created Wikipedia; its aim is to create a set of map data that's free to use, editable, and licensed under new copyright schemes.
Abstract: The OpenStreetMap project is a knowledge collective that provides user-generated street maps. OSM follows the peer production model that created Wikipedia; its aim is to create a set of map data that's free to use, editable, and licensed under new copyright schemes. A considerable number of contributors edit the world map collaboratively using the OSM technical infrastructure, and a core group, estimated at approximately 40 volunteers, dedicate their time to creating and improving OSM's infrastructure, including maintaining the server, writing the core software that handles the transactions with the server, and creating cartographical outputs. There's also a growing community of software developers who develop software tools to make OSM data available for further use across different application domains, software platforms, and hardware devices. The OSM project's hub is the main OSM Web site.
2,487 citations
TL;DR: These findings demonstrate the feasibility of developing standardized definitions of BCTs included in behavioral interventions and highlight problematic variability in the reporting of intervention content.
Abstract: Objective: Without standardized definitions of the techniques included in behavior change interventions, it is difficult to faithfully replicate effective interventions and challenging to identify techniques contributing to effectiveness across interventions. This research aimed to develop and test a theory-linked taxonomy of generally applicable behavior change techniques (BCTs). Design: Twenty-six BCTs were defined. Two psychologists used a 5-page coding manual to independently judge the presence or absence of each technique in published intervention descriptions and in intervention manuals. Results: Three systematic reviews yielded 195 published descriptions. Across 78 reliability tests (i.e., 26 techniques applied to 3 reviews), the average kappa per technique was 0.79, with 93% of judgments being agreements. Interventions were found to vary widely in the range and type of techniques used, even when targeting the same behavior among similar participants. The average agreement for intervention manuals was 85%, and a comparison of BCTs identified in 13 manuals and 13 published articles describing the same interventions generated a technique correspondence rate of 74%, with most mismatches (73%) arising from identification of a technique in the manual but not in the article. Conclusions: These findings demonstrate the feasibility of developing standardized definitions of BCTs included in behavioral interventions and highlight problematic variability in the reporting of intervention content.
2,321 citations
TL;DR: The LHCb experiment is dedicated to precision measurements of CP violation and rare decays of B hadrons at the Large Hadron Collider (LHC) at CERN (Geneva).
Abstract: The LHCb experiment is dedicated to precision measurements of CP violation and rare decays of B hadrons at the Large Hadron Collider (LHC) at CERN (Geneva). The initial configuration and expected performance of the detector and associated systems, as established by test beam measurements and simulation studies, is described.
2,286 citations
TL;DR: Three young adult patients with early-onset, severe retinal dystrophy were administered subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human R PE65 promoter.
Abstract: Early-onset, severe retinal dystrophy caused by mutations in the gene encoding reti- nal pigment epithelium-specific 65-kDa protein (RPE65) is associated with poor vi- sion at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Gold- mann perimetry in any of the three patients. We detected no change in retinal re- sponses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747.)
1,912 citations
TL;DR: A systematic review and meta-analysis of the prevalence of mental disorder, substance misuse, suicide, suicidal ideation and deliberate self harm in LGB people revealed that lesbian and bisexual women were particularly at risk of substance dependence.
Abstract: Lesbian, gay and bisexual (LGB) people may be at higher risk of mental disorders than heterosexual people. We conducted a systematic review and meta-analysis of the prevalence of mental disorder, substance misuse, suicide, suicidal ideation and deliberate self harm in LGB people. We searched Medline, Embase, PsycInfo, Cinahl, the Cochrane Library Database, the Web of Knowledge, the Applied Social Sciences Index and Abstracts, the International Bibliography of the Social Sciences, Sociological Abstracts, the Campbell Collaboration and grey literature databases for articles published January 1966 to April 2005. We also used Google and Google Scholar and contacted authors where necessary. We searched all terms related to homosexual, lesbian and bisexual people and all terms related to mental disorders, suicide, and deliberate self harm. We included papers on population based studies which contained concurrent heterosexual comparison groups and valid definition of sexual orientation and mental health outcomes. Of 13706 papers identified, 476 were initially selected and 28 (25 studies) met inclusion criteria. Only one study met all our four quality criteria and seven met three of these criteria. Data was extracted on 214,344 heterosexual and 11,971 non heterosexual people. Meta-analyses revealed a two fold excess in suicide attempts in lesbian, gay and bisexual people [pooled risk ratio for lifetime risk 2.47 (CI 1.87, 3.28)]. The risk for depression and anxiety disorders (over a period of 12 months or a lifetime) on meta-analyses were at least 1.5 times higher in lesbian, gay and bisexual people (RR range 1.54–2.58) and alcohol and other substance dependence over 12 months was also 1.5 times higher (RR range 1.51–4.00). Results were similar in both sexes but meta analyses revealed that lesbian and bisexual women were particularly at risk of substance dependence (alcohol 12 months: RR 4.00, CI 2.85, 5.61; drug dependence: RR 3.50, CI 1.87, 6.53; any substance use disorder RR 3.42, CI 1.97–5.92), while lifetime prevalence of suicide attempt was especially high in gay and bisexual men (RR 4.28, CI 2.32, 7.88). LGB people are at higher risk of mental disorder, suicidal ideation, substance misuse, and deliberate self harm than heterosexual people.
TL;DR: It is proved that the method for learning sparse representations shared across multiple tasks is equivalent to solving a convex optimization problem for which there is an iterative algorithm which converges to an optimal solution.
Abstract: We present a method for learning sparse representations shared across multiple tasks. This method is a generalization of the well-known single-task 1-norm regularization. It is based on a novel non-convex regularizer which controls the number of learned features common across the tasks. We prove that the method is equivalent to solving a convex optimization problem for which there is an iterative algorithm which converges to an optimal solution. The algorithm has a simple interpretation: it alternately performs a supervised and an unsupervised step, where in the former step it learns task-specific functions and in the latter step it learns common-across-tasks sparse representations for these functions. We also provide an extension of the algorithm which learns sparse nonlinear representations using kernels. We report experiments on simulated and real data sets which demonstrate that the proposed method can both improve the performance relative to learning each task independently and lead to a few learned features common across related tasks. Our algorithm can also be used, as a special case, to simply select--not learn--a few common variables across the tasks.
TL;DR: The supplementary motor complex consists of the supplementary motor area, the supplementary eye field and the pre-supplementary motor area and theories regarding their function vary widely.
Abstract: The supplementary motor complex consists of the supplementary motor area, the supplementary eye field and the pre-supplementary motor area. In recent years, these areas have come under increasing scrutiny from cognitive neuroscientists, motor physiologists and clinicians because they seem to be crucial for linking cognition to action. However, theories regarding their function vary widely. This Review brings together the data regarding the supplementary motor regions, highlighting outstanding issues and providing new perspectives for understanding their functions.
01 Sep 2008-International Journal of Human-computer Studies \/ International Journal of Man-machine Studies
TL;DR: Overall the findings suggest that immersion can be measured subjectively as well as objectively (task completion time, eye movements) and negative emotions and uneasiness also run high.
Abstract: Despite the word's common usage by gamers and reviewers alike, it is still not clear what immersion means. This paper explores immersion further by investigating whether immersion can be defined quantitatively, describing three experiments in total. The first experiment investigated participants' abilities to switch from an immersive to a non-immersive task. The second experiment investigated whether there were changes in participants' eye movements during an immersive task. The third experiment investigated the effect of an externally imposed pace of interaction on immersion and affective measures (state anxiety, positive affect, negative affect). Overall the findings suggest that immersion can be measured subjectively (through questionnaires) as well as objectively (task completion time, eye movements). Furthermore, immersion is not only viewed as a positive experience: negative emotions and uneasiness (i.e. anxiety) also run high.
TL;DR: In this paper, a list of techniques and definitions was generated from techniques published in two systematic reviews, supplemented by "brainstorming" and a systematic search of nine textbooks used in training applied psychologists.
Abstract: Theory provides a helpful basis for designing interventions to change behaviour but offers little guidance on how to do this. This paper aims to illustrate methods for developing an extensive list of behaviour change techniques (with definitions) and for linking techniques to theoretical constructs. A list of techniques and definitions was generated from techniques published in two systematic reviews, supplemented by “brainstorming” and a systematic search of nine textbooks used in training applied psychologists. Inter-rater reliability of extracting the techniques and definitions from the textbooks was assessed. Four experts judged which techniques would be effective in changing 11 theoretical constructs associated with behaviour change.
Thirty-five techniques identified in the reviews were extended to 53 by brainstorming and to 137 by consulting textbooks. Agreement for the 53 definitions was 74.7 per cent (15.4% cells completed and 59.3% cells empty for both raters). Agreement about the link between the 35 techniques and theoretical constructs was 71.7 per cent of 385 judgments (12.2% agreement that effective and 59.5% agreement that not effective). This preliminary work demonstrates the possibility of developing a comprehensive, reliable taxonomy of techniques linked to theory. Further refinement is needed to eliminate redundancies, resolve uncertainties, and complete technique definitions.
Broad Institute1, Harvard University2, Massachusetts Institute of Technology3, Cardiff University4, University College London5, University of Edinburgh6, Trinity College, Dublin7, Karolinska Institutet8, Uppsala University9, University of Southern California10, University of Aberdeen11, University of North Carolina at Chapel Hill12, QIMR Berghofer Medical Research Institute13, Royal College of Surgeons in Ireland14, National Health Service15, University of Oxford16, Queen Mary University of London17, State University of New York System18, University of Coimbra19
TL;DR: A genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls provides strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.
Abstract: Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants ( CNVs) have been identified in individual patients with schizophrenia(2-7) and also in neurodevelopmental disorders(8-11), but large- scale genome- wide surveys have not been performed. Here we report a genome- wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high- density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15- fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single- occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo- cardio- facial syndrome, which includes psychotic symptoms in 30% of patients(12). Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome- wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome- wide and at specific loci.
TL;DR: The medial prefrontal cortex and the superior temporal sulcus as mentioned in this paper show altered activity during the performance of social cognitive tasks, such as face recognition and mental-state attribution, during adolescence.
Abstract: The term 'social brain' refers to the network of brain regions that are involved in understanding others. Behaviour that is related to social cognition changes dramatically during human adolescence. This is paralleled by functional changes that occur in the social brain during this time, in particular in the medial prefrontal cortex and the superior temporal sulcus, which show altered activity during the performance of social cognitive tasks, such as face recognition and mental-state attribution. Research also indicates that, in humans, these parts of the social brain undergo structural development, including synaptic reorganization, during adolescence. Bringing together two relatively new and rapidly expanding areas of neuroscience--social neuroscience and the study of brain development during adolescence--will increase our understanding of how the social brain develops during adolescence.
University College London1, Imperial College London2, University of London3, Erasmus University Rotterdam4, French Institute of Health and Medical Research5, Albert Einstein College of Medicine6, Norwegian University of Science and Technology7, University of Washington8, University of Barcelona9, New York State Department of Health10, Monash University11, University of Toronto12, Mayo Clinic13, Mater Misericordiae University Hospital14, UCL Institute of Neurology15, University of Tübingen16
TL;DR: Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD, but this knowledge should be applied with caution in the diagnosis and counselling of patients.
Abstract: Summary Background Mutations in LRRK2 , the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2 -associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2 ? Methods Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2 -associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. Findings Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2 -associated PD were more benign than those of idiopathic PD. Interpretation Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. Funding UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.
TL;DR: Positive psychological well-being was significantly associated with reduced cardiovascular mortality in healthy population studies, and with reduced death rates in patients with renal failure and with human immunodeficiency virus-infection.
Abstract: Objective: To review systematically prospective, observational, cohort studies of the association between positive well-being and mortality using meta-analytic methods. Recent years have witnessed increased interest in the relationship between positive psychological well-being and physical health. Methods: We searched general bibliographic databases: Medline, PsycINFO, Web of Science, and PubMed up to January 2008. Two reviewers independently extracted data on Study characteristics, quality, and estimates of associations. Results: There were 35 studies (26 articles) investigating mortality in initially healthy Populations and 35 studies (28 articles) of disease populations. The meta-analyses showed that positive psychological well-being was associated with reduced mortality in both the healthy population (combined hazard ratio (HR) = 0.82; 95% Confidence Interval (Cl) = 0.76-0.89; p < .001) and the disease Population (combined FIR = 0.98; CI = 0.95-1.00; p = .030) studies. There were indications Of publication bias in this literature, although the fail-safe numbers were 2444 and 1397 for healthy and disease Population studies,, respectively. Intriguingly, meta-analysis of studies that controlled for negative affect showed that the protective effects of positive psychological well-being were independent of negative affect. Both positive affect (e.g., emotional well-being, positive mood, joy, happiness, vigor, energy) and positive trait-like dispositions (e.g., life satisfaction, hopefulness, optimism, sense of humor) were associated with reduced mortality in healthy population Studies. Positive psychological well-being was significantly associated with reduced cardiovascular mortality in healthy population studies, and with reduced death rates in patients with renal failure and with human immunodeficiency virus-infection. Conclusions: The Current review suggests that positive psychological well-being has a favorable effect on survival in both healthy and diseased populations.
TL;DR: This review explores to what extent descending pathways are highly conserved across species and concludes that there are actually rather widespread species differences, for example, in the transmission of information from the corticospinal tract to upper limb motoneurons.
Abstract: Each of the descending pathways involved in motor control has a number of anatomical, molecular, pharmacological, and neuroinformatic characteristics. They are differentially involved in motor control, a process that results from operations involving the entire motor network rather than from the brain commanding the spinal cord. A given pathway can have many functional roles. This review explores to what extent descending pathways are highly conserved across species and concludes that there are actually rather widespread species differences, for example, in the transmission of information from the corticospinal tract to upper limb motoneurons. The significance of direct, corticomotoneuronal (CM) connections, which were discovered a little more than 50 years ago, is reassessed. I conclude that although these connections operate in parallel with other less direct linkages to motoneurons, CM influence is significant and may subserve some special functions including adaptive motor behaviors involving the distal extremities.
TL;DR: Using the analytical solution an upper bound on the number of taps required to compensate chromatic dispersion is obtained, with simulation revealing an improved bound of 2.2 taps per 1000ps/nm for 10.7GBaud data.
Abstract: Digital filters underpin the performance of coherent optical receivers which exploit digital signal processing (DSP) to mitigate transmission impairments. We outline the principles of such receivers and review our experimental investigations into compensation of polarization mode dispersion. We then consider the details of the digital filtering employed and present an analytical solution to the design of a chromatic dispersion compensating filter. Using the analytical solution an upper bound on the number of taps required to compensate chromatic dispersion is obtained, with simulation revealing an improved bound of 2.2 taps per 1000ps/nm for 10.7GBaud data. Finally the principles of digital polarization tracking are outlined and through simulation, it is demonstrated that 100krad/s polarization rotations could be tracked using DSP with a clock frequency of less than 500MHz.
Cardiff University1, University of Birmingham2, Broad Institute3, University of Pittsburgh4, University of Pennsylvania5, Harvard University6, University of Aberdeen7, King's College London8, Trinity College, Dublin9, Royal Edinburgh Hospital10, University College London11, Royal Victoria Infirmary12
TL;DR: The results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder and found further support for the previously reported CACNA1C.
Abstract: To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.
TL;DR: It is shown that transmembrane protein 16A (TMEM16A), which is also called anoctamin 1 (ANO1), is a bona fide Ca2+-activated chloride channel that is activated by intracellular Ca2- and Ca2+, and defines a new family of ionic channels.
Abstract: Calcium (Ca2+)-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca2+-activated chloride channel that is activated by intracellular Ca2+ and Ca2+-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca2+-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca2+-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca2+-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes. Calcium-activated chloride channels play a fundamental role in many physiological processes, but their molecular identity has so far evaded characterization. This paper shows that the transmembrane protein TMEM16A, also known as anoctamin 1 or ANO1, is a Ca2+-activated chloride channel. TMEM16A has a novel trimeric structure composed of eight transmembrane domains, very different from all previously characterized ionic channels. Its knock-down reduced native Ca2+activated chloride currents and impairs salivary secretion in mice.
TL;DR: The occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by insertional mutagenesis in a completed gene therapy trial of 10 SCID-X1 patients is described and a general toxicity of endogenous gammaretroviral enhancer elements is highlighted.
Abstract: X-linked SCID (SCID-X1) is amenable to correction by gene therapy using conventional gammaretroviral vectors. Here, we describe the occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by insertional mutagenesis in a completed gene therapy trial of 10 SCID-X1 patients. Integration of the vector in an antisense orientation 35 kb upstream of the protooncogene LIM domain only 2 (LMO2) caused overexpression of LMO2 in the leukemic clone. However, leukemogenesis was likely precipitated by the acquisition of other genetic abnormalities unrelated to vector insertion, including a gain-of-function mutation in NOTCH1, deletion of the tumor suppressor gene locus cyclin-dependent kinase 2A (CDKN2A), and translocation of the TCR-β region to the STIL-TAL1 locus. These findings highlight a general toxicity of endogenous gammaretroviral enhancer elements and also identify a combinatorial process during leukemic evolution that will be important for risk stratification and for future protocol design.
TL;DR: This paper presents an integrated theory of how cities evolve, linking urban economics and transportation behavior to developments in network science, allometric growth, and fractal geometry, which provides new insights into the resource limits facing cities in terms of the meaning of density, compactness, and sprawl.
Abstract: Despite a century of effort, our understanding of how cities evolve is still woefully inadequate. Recent research, however, suggests that cities are complex systems that mainly grow from the bottom up, their size and shape following well-defined scaling laws that result from intense competition for space. An integrated theory of how cities evolve, linking urban economics and transportation behavior to developments in network science, allometric growth, and fractal geometry, is being slowly developed. This science provides new insights into the resource limits facing cities in terms of the meaning of density, compactness, and sprawl, and related questions of sustainability. It has the potential to enrich current approaches to city planning and replace traditional top-down strategies with realistic city plans that benefit all city dwellers.
TL;DR: The neural control of micturition is reviewed and how disruption of this control leads to abnormal storage and release of urine.
Abstract: Micturition, or urination, occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. The neural circuitry that controls this process is complex and highly distributed: it involves pathways at many levels of the brain, the spinal cord and the peripheral nervous system and is mediated by multiple neurotransmitters. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary or reflex micturition, leading to urinary incontinence. This is a major health problem, especially in those with neurological impairment. Here we review the neural control of micturition and how disruption of this control leads to abnormal storage and release of urine.
TL;DR: Observations suggest an enrichment of both IL-17+CD4+ and CD8+ T cells in active MS lesions as well as an important role for IL- 17 in MS pathogenesis, with some remarkable differences from the experimental autoimmune encephalomyelitis model.
Abstract: Recent findings in the animal model for multiple sclerosis (MS), experimental autoimmune encephalomyelitis, implicate a novel CD4+ T-cell subset (TH17), characterized by the secretion of interleukin-17 (IL-17), in disease pathogenesis. To elucidate its role in MS, brain tissues from patients with MS were compared to controls. We detected expression of IL-17 mRNA (by in situ hybridization) and protein (by immunohistochemistry) in perivascular lymphocytes as well as in astrocytes and oligodendrocytes located in the active areas of MS lesions. Further, we found a significant increase in the number of IL-17+ T cells in active rather than inactive areas of MS lesions. Specifically, double immunofluorescence showed that IL-17 immunoreactivity was detected in 79% of T cells in acute lesions, 73% in active areas of chronic active lesions, but in only 17% of those in inactive lesions and 7% in lymph node control tissue. CD8+, as well as CD4+, T cells were equally immunostained for IL-17 in MS tissues. Interestingly, and in contrast to lymph node T cells, no perivascular T cells showed FoxP3 expression, a marker of regulatory T cells, at any stage of MS lesions. These observations suggest an enrichment of both IL-17+CD4+ and CD8+ T cells in active MS lesions as well as an important role for IL-17 in MS pathogenesis, with some remarkable differences from the experimental autoimmune encephalomyelitis model.
French Institute of Health and Medical Research1, University of Naples Federico II2, Institut Gustave Roussy3, University of Paris-Sud4, University of Rome Tor Vergata5, Boston Children's Hospital6, Centre national de la recherche scientifique7, University of Gothenburg8, Foundation for Research & Technology – Hellas9, University of Ferrara10, Stony Brook University11, University of Graz12, University College London13
TL;DR: Evidence is provided of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53, which improved the survival of p 53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels.
Abstract: Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.
TL;DR: A set of energy minimization benchmarks are described and used to compare the solution quality and runtime of several common energy minimizations algorithms and a general-purpose software interface is provided that allows vision researchers to easily switch between optimization methods.
Abstract: Among the most exciting advances in early vision has been the development of efficient energy minimization algorithms for pixel-labeling tasks such as depth or texture computation. It has been known for decades that such problems can be elegantly expressed as Markov random fields, yet the resulting energy minimization problems have been widely viewed as intractable. Algorithms such as graph cuts and loopy belief propagation (LBP) have proven to be very powerful: For example, such methods form the basis for almost all the top-performing stereo methods. However, the trade-offs among different energy minimization algorithms are still not well understood. In this paper, we describe a set of energy minimization benchmarks and use them to compare the solution quality and runtime of several common energy minimization algorithms. We investigate three promising methods-graph cuts, LBP, and tree-reweighted message passing-in addition to the well-known older iterated conditional mode (ICM) algorithm. Our benchmark problems are drawn from published energy functions used for stereo, image stitching, interactive segmentation, and denoising. We also provide a general-purpose software interface that allows vision researchers to easily switch between optimization methods. The benchmarks, code, images, and results are available at http://vision.middlebury.edu/MRF/.
20 Oct 2008
TL;DR: This work proposes an algorithm for semantic segmentation based on 3D point clouds derived from ego-motion that works well on sparse, noisy point clouds, and unlike existing approaches, does not need appearance-based descriptors.
Abstract: We propose an algorithm for semantic segmentation based on 3D point clouds derived from ego-motion. We motivate five simple cues designed to model specific patterns of motion and 3D world structure that vary with object category. We introduce features that project the 3D cues back to the 2D image plane while modeling spatial layout and context. A randomized decision forest combines many such features to achieve a coherent 2D segmentation and recognize the object categories present. Our main contribution is to show how semantic segmentation is possible based solely on motion-derived 3D world structure. Our method works well on sparse, noisy point clouds, and unlike existing approaches, does not need appearance-based descriptors.
Experiments were performed on a challenging new video database containing sequences filmed from a moving car in daylight and at dusk. The results confirm that indeed, accurate segmentation and recognition are possible using only motion and 3D world structure. Further, we show that the motion-derived information complements an existing state-of-the-art appearance-based method, improving both qualitative and quantitative performance.