2,579 research outputs found
A joint inversion of receiver function and Rayleigh wave phase velocity dispersion data to estimate crustal structure in West Antarctica
We determine crustal shear-wave velocity structure and crustal thickness at recently deployed seismic stations across West Antarctica, using a joint inversion of receiver functions and fundamental mode Rayleigh wave phase velocity dispersion. The stations are from both the UK Antarctic Network (UKANET) and Polar Earth Observing Network/Antarctic Network (POLENET/ANET). The former include, for the first time, 4 stations along the spine of the Antarctic Peninsula, 3 in the Ellsworth Land and 5 stations in the vicinity of the Pine Island Rift. Within the West Antarctic Rift System (WARS) we model a crustal thickness range of 18-28 km, and show that the thinnest crust (βΌ18 km) is in the vicinity of the Byrd Subglacial Basin and Bentley Subglacial Trench. In these regions we also find the highest ratio of fast (Vs = 4.0-4.3 km/s) (likely mafic) lower crust to felsic/intermediate upper crust. The thickest mafic lower crust we model is in Ellsworth Land, a critical area for constraining the eastern limits of the WARS. Although we find thinner crust in this region (βΌ30 km) than in the neighbouring Antarctic Peninsula and Haag-Ellsworth Whitmore block (HEW), the Ellsworth Land crust has not undergone as much extension as the central WARS. This suggests that the WARS does not link with the Weddell Sea Rift System through Ellsworth Land, and instead has progressed during its formation towards the Bellingshausen and Amundsen Sea Embayments. We also find that the thin WARS crust extends towards the Pine Island Rift, suggesting that the boundary between the WARS and the Thurston Island block lies in this region, βΌ200 km north of its previously accepted position. The thickest crust (38-40 km) we model in this study is in the Ellsworth Mountain section of the HEW block. We find thinner crust (30-33 km) in the Whitmore Mountains and Haag Nunatak sectors of the HEW, consistent with the composite nature of the block. In the Antarctic Peninsula we find a crustal thickness range of 30-38 km and a likely dominantly felsic/intermediate crustal composition. By forward modelling high frequency receiver functions we also assess if any thick, low velocity subglacial sediment accumulations are present, and find a 0.1-0.8 km thick layer at 10 stations within the WARS, Thurston Island and Ellsworth Land. We suggest that these units of subglacial sediment could provide a source region for the soft basal till layers found beneath numerous outlet glaciers, and may act to accelerate ice flow
Meaning behind measurement : self-comparisons affect responses to health related quality of life questionnaires
Purpose The subjective nature of quality of life is particularly pertinent to the domain of health-related quality of
life (HRQOL) research. The extent to which participantsβ responses are affected by subjective information and personal reference frames is unknown. This study investigated how an elderly population living with a chronic metabolic bone disorder evaluated self-reported quality of life. Methods Participants (n = 1,331) in a multi-centre randomised controlled trial for the treatment of Pagetβs disease completed annual HRQOL questionnaires, including the SF-36, EQ-5D and HAQ. Supplementary questions were added to reveal implicit reference frames used when making HRQOL evaluations. Twenty-one participants (11 male, 10 female, aged 59β91 years) were interviewed retrospectively about their responses to the supplementary questions, using cognitive interviewing techniques and semi-structured topic guides. Results The interviews revealed that participants used complex and interconnected reference frames to promote response shift when making quality of life evaluations. The choice of reference frame often reflected external factors unrelated to individual health. Many participants also stated that they were unclear whether to report general or disease-related HRQOL. Conclusions It is important, especially in clinical trials, to provide instructions clarifying whether βquality of lifeβ refers to disease-related HRQOL. Information on selfcomparison reference frames is necessary for the interpretation of responses to questions about HRQOL.The Chief Scientist Office of the Scottish Government Health Directorates,
The PRISM funding bodies (the Arthritis Research Campaign, the National Association for the Relief of Pagetβs disease and the Alliance for Better Bone Health)Peer reviewedAuthor final versio
A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia
Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cellβresistant cell lines. To translate this finding to the clinic, CNDO-109βactivated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3βΓβ105 (nβ=β3), 1βΓβ106 (nβ=β3), and 3βΓβ106 (nβ=β6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3βΓβ105), 156 (1βΓβ106), and 337 (3βΓβ106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+βmonths were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted
The Human Fungal Pathogen Cryptococcus neoformans Escapes Macrophages by a Phagosome Emptying Mechanism That Is Inhibited by Arp2/3 Complex-Mediated Actin Polymerisation
The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin βflashesβ occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism.\ud
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"It's making contacts" : notions of social capital and implications for widening access to medical education
Acknowledgements Our thanks to the Medical Schools Council (MSC) of the UK for funding Study A; REACH Scotland for funding Study B; and Queen Mary University of London, and to the medical school applicants and students who gave their time to be interviewed. Our thanks also to Dr Sean Zhou and Dr Sally Curtis, and Manjul Medhi, for their help with data collection for studies A and B respectively. Our thanks also to Dr Lara Varpio, Uniformed Services University of the USA, for her advice and guidance on collating data sets and her comments on the draft manuscript.Peer reviewedPublisher PD
Dealing with missing data in a multi-question depression scale: a comparison of imputation methods
BACKGROUND: Missing data present a challenge to many research projects. The problem is often pronounced in studies utilizing self-report scales, and literature addressing different strategies for dealing with missing data in such circumstances is scarce. The objective of this study was to compare six different imputation techniques for dealing with missing data in the Zung Self-reported Depression scale (SDS). METHODS: 1580 participants from a surgical outcomes study completed the SDS. The SDS is a 20 question scale that respondents complete by circling a value of 1 to 4 for each question. The sum of the responses is calculated and respondents are classified as exhibiting depressive symptoms when their total score is over 40. Missing values were simulated by randomly selecting questions whose values were then deleted (a missing completely at random simulation). Additionally, a missing at random and missing not at random simulation were completed. Six imputation methods were then considered; 1) multiple imputation, 2) single regression, 3) individual mean, 4) overall mean, 5) participant's preceding response, and 6) random selection of a value from 1 to 4. For each method, the imputed mean SDS score and standard deviation were compared to the population statistics. The Spearman correlation coefficient, percent misclassified and the Kappa statistic were also calculated. RESULTS: When 10% of values are missing, all the imputation methods except random selection produce Kappa statistics greater than 0.80 indicating 'near perfect' agreement. MI produces the most valid imputed values with a high Kappa statistic (0.89), although both single regression and individual mean imputation also produced favorable results. As the percent of missing information increased to 30%, or when unbalanced missing data were introduced, MI maintained a high Kappa statistic. The individual mean and single regression method produced Kappas in the 'substantial agreement' range (0.76 and 0.74 respectively). CONCLUSION: Multiple imputation is the most accurate method for dealing with missing data in most of the missind data scenarios we assessed for the SDS. Imputing the individual's mean is also an appropriate and simple method for dealing with missing data that may be more interpretable to the majority of medical readers. Researchers should consider conducting methodological assessments such as this one when confronted with missing data. The optimal method should balance validity, ease of interpretability for readers, and analysis expertise of the research team
Neurogenesis Drives Stimulus Decorrelation in a Model of the Olfactory Bulb
The reshaping and decorrelation of similar activity patterns by neuronal
networks can enhance their discriminability, storage, and retrieval. How can
such networks learn to decorrelate new complex patterns, as they arise in the
olfactory system? Using a computational network model for the dominant neural
populations of the olfactory bulb we show that fundamental aspects of the adult
neurogenesis observed in the olfactory bulb -- the persistent addition of new
inhibitory granule cells to the network, their activity-dependent survival, and
the reciprocal character of their synapses with the principal mitral cells --
are sufficient to restructure the network and to alter its encoding of odor
stimuli adaptively so as to reduce the correlations between the bulbar
representations of similar stimuli. The decorrelation is quite robust with
respect to various types of perturbations of the reciprocity. The model
parsimoniously captures the experimentally observed role of neurogenesis in
perceptual learning and the enhanced response of young granule cells to novel
stimuli. Moreover, it makes specific predictions for the type of odor
enrichment that should be effective in enhancing the ability of animals to
discriminate similar odor mixtures
Rapid Change in Articulatory Lip Movement Induced by Preceding Auditory Feedback during Production of Bilabial Plosives
BACKGROUND: There has been plentiful evidence of kinesthetically induced rapid compensation for unanticipated perturbation in speech articulatory movements. However, the role of auditory information in stabilizing articulation has been little studied except for the control of voice fundamental frequency, voice amplitude and vowel formant frequencies. Although the influence of auditory information on the articulatory control process is evident in unintended speech errors caused by delayed auditory feedback, the direct and immediate effect of auditory alteration on the movements of articulators has not been clarified. METHODOLOGY/PRINCIPAL FINDINGS: This work examined whether temporal changes in the auditory feedback of bilabial plosives immediately affects the subsequent lip movement. We conducted experiments with an auditory feedback alteration system that enabled us to replace or block speech sounds in real time. Participants were asked to produce the syllable /pa/ repeatedly at a constant rate. During the repetition, normal auditory feedback was interrupted, and one of three pre-recorded syllables /pa/, /Ξ¦a/, or /pi/, spoken by the same participant, was presented once at a different timing from the anticipated production onset, while no feedback was presented for subsequent repetitions. Comparisons of the labial distance trajectories under altered and normal feedback conditions indicated that the movement quickened during the short period immediately after the alteration onset, when /pa/ was presented 50 ms before the expected timing. Such change was not significant under other feedback conditions we tested. CONCLUSIONS/SIGNIFICANCE: The earlier articulation rapidly induced by the progressive auditory input suggests that a compensatory mechanism helps to maintain a constant speech rate by detecting errors between the internally predicted and actually provided auditory information associated with self movement. The timing- and context-dependent effects of feedback alteration suggest that the sensory error detection works in a temporally asymmetric window where acoustic features of the syllable to be produced may be coded
Using observational data to estimate an upper bound on the reduction in cancer mortality due to periodic screening
BACKGROUND: Because randomized cancer screening trials are very expensive, observational cancer screening studies can play an important role in the early phases of screening evaluation. Periodic screening evaluation (PSE) is a methodology for estimating the reduction in population cancer mortality from data on subjects who receive regularly scheduled screens. Although PSE does not require assumptions about natural history of cancer it requires other assumptions, particularly progressive detection β the assumption that once a cancer is detected by a screening test, it will always be detected by the screening test. METHODS: We formulate a simple version of PSE and show that it leads to an upper bound on screening efficacy if the progressive detection assumption does not hold (and any effect of birth cohort is minimal) To determine if the upper bound is reasonable, for three randomized screening trials, we compared PSE estimates based only on screened subjects with PSE estimates based on all subjects. RESULTS: In the three randomized screening trials, PSE estimates based on screened subjects gave fairly close results to PSE estimates based on all subjects. CONCLUSION: PSE has promise for obtaining an upper bound on the reduction in population cancer mortality rates based on observational screening data. If the upper bound estimate is found to be small and any birth cohort effects are likely minimal, then a definitive randomized trial would not be warranted
A model of direction selectivity in the starburst amacrine cell network
Displaced starburst amacrine cells (SACs) are retinal interneurons that exhibit GABAA receptor-mediated and Clβ cotransporter-mediated, directionally selective (DS) light responses in the rabbit retina. They depolarize to stimuli that move centrifugally through the receptive field surround and hyperpolarize to stimuli that move centripetally through the surround (Gavrikov et al, PNAS 100(26):16047β16052, 2003, PNAS 103(49):18793β18798, 2006). They also play a key role in the activity of DS ganglion cells (DS GC; Amthor et al, Vis Neurosci 19:495β509 2002; Euler et al, Nature 418:845β852, 2002; Fried et al, Nature 420:411β 414, 2002; Gavrikov et al, PNAS 100(26):16047β16052, 2003, PNAS 103(49):18793β18798, 2006; Lee and Zhou, Neuron 51:787β799 2006; Yoshida et al, Neuron 30:771β780, 2001). In this paper we present a model of strong DS behavior of SACs which relies on the GABA-mediated communication within a tightly interconnected network of these cells and on the glutamate signal that the SACs receive from bipolar cells (a presynaptic cell that receives input from cones). We describe how a moving light stimulus can produce a large, sustained depolarization of the SAC dendritic tips that point in the direction that the stimulus moves (i.e., centrifugal motion), but produce a minimal depolarization of the dendritic tips that point in the opposite direction (i.e., centripetal motion). This DS behavior, which is quantified based on the relative size and duration of the depolarizations evoked by stimulus motion at dendritic tips pointing in opposite directions, is robust to changes of many different parameter values and consistent with experimental data. In addition, the DS behavior is strengthened under the assumptions that the Clβ cotransporters Naβ+β-Kβ+β-Clββ and Kβ+β-Clββ are located in different regions of the SAC dendritic tree (Gavrikov et al, PNAS 103(49):18793β18798, 2006) and that GABA evokes a long-lasting response (Gavrikov et al, PNAS 100(26):16047β16052, 2003, PNAS 103(49):18793β18798, 2006; Lee and Zhou, Neuron 51:787β799, 2006). A possible mechanism is discussed based on the generation of waves of local glutamate and GABA secretion, and their postsynaptic interplay as the waves travel between cell compartments
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