1,178 research outputs found
Inhibition of interleukin 6 signalling and renal function: a Mendelian randomization study.
Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD), but the direct effects of IL-6 inhibition on renal function are not known. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse-variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR-Egger methods. There was no evidence for an association of genetically proxied inhibition of IL-6 signalling (scaled per standard deviation unit decrease in C-reactive protein) with log eGFR (0.001, 95% confidence interval -0.004 - 0.007), BUN (0.009, 95% confidence interval -0.003 - 0.021) and CKD (odds ratio 0.948, 95% confidence interval 0.822 - 1.094). These findings do not raise concerns for IL-6 signalling having large adverse effects on renal function
Characterisation of neonatal seizures and their treatment using continuous EEG monitoring: a multicentre experience.
OBJECTIVE: The aim of this multicentre study was to describe detailed characteristics of electrographic seizures in a cohort of neonates monitored with multichannel continuous electroencephalography (cEEG) in 6 European centres. METHODS: Neonates of at least 36âweeks of gestation who required cEEG monitoring for clinical concerns were eligible, and were enrolled prospectively over 2âyears from June 2013. Additional retrospective data were available from two centres for January 2011 to February 2014. Clinical data and EEGs were reviewed by expert neurophysiologists through a central server. RESULTS: Of 214 neonates who had recordings suitable for analysis, EEG seizures were confirmed in 75 (35%). The most common cause was hypoxic-ischaemic encephalopathy (44/75, 59%), followed by metabolic/genetic disorders (16/75, 21%) and stroke (10/75, 13%). The median number of seizures was 24 (IQR 9-51), and the median maximum hourly seizure burden in minutes per hour (MSB) was 21âmin (IQR 11-32), with 21 (28%) having status epilepticus defined as MSB>30âmin/hour. MSB developed later in neonates with a metabolic/genetic disorder. Over half (112/214, 52%) of the neonates were given at least one antiepileptic drug (AED) and both overtreatment and undertreatment was evident. When EEG monitoring was ongoing, 27 neonates (19%) with no electrographic seizures received AEDs. Fourteen neonates (19%) who did have electrographic seizures during cEEG monitoring did not receive an AED. CONCLUSIONS: Our results show that even with access to cEEG monitoring, neonatal seizures are frequent, difficult to recognise and difficult to treat. OBERSERVATION STUDY NUMBER: NCT02160171
Effects of a recombinant gene expression on ColE1-like plasmid segregation in Escherichia coli
<p>Abstract</p> <p>Background</p> <p>Segregation of expression plasmids leads to loss of recombinant DNA from transformed bacterial cells due to the irregular distribution of plasmids between the daughter cells during cell division. Under non-selective conditions this segregational instability results in a heterogeneous population of cells, where the non-productive plasmid-free cells overgrow the plasmid-bearing cells thus decreasing the yield of recombinant protein. Amongst the factors affecting segregational plasmid instability are: the plasmid design, plasmid copy-number, host cell genotype, fermentation conditions etc. This study aims to investigate the influence of transcription and translation on the segregation of recombinant plasmids designed for constitutive gene expression in <it>Escherichia coli </it>LE392 at glucose-limited continuous cultivation. To this end a series of pBR322-based plasmids carrying a synthetic human interferon-gamma (hIFNÎł) gene placed under the control of different regulatory elements (promoter and ribosome-binding sites) were used as a model.</p> <p>Results</p> <p>Bacterial growth and product formation kinetics of transformed <it>E. coli </it>LE392 cells cultivated continuously were described by a structured kinetic model proposed by Lee et al. (1985). The obtained results demonstrated that both transcription and translation efficiency strongly affected plasmid segregation. The segregation of plasmid having a deleted promoter did not exceed 5% after 190 h of cultivation. The observed high plasmid stability was not related with an increase in the plasmid copy-number. A reverse correlation between the yield of recombinant protein (as modulated by using different ribosome binding sites) and segregational plasmid stability (determined by the above model) was also observed.</p> <p>Conclusions</p> <p>Switching-off transcription of the hIFNÎł gene has a stabilising effect on ColE1-like plasmids against segregation, which is not associated with an increase in the plasmid copy-number. The increased constitutive gene expression has a negative effect on segregational plasmid stability. A kinetic model proposed by Lee et al. (1985) was appropriate for description of <it>E. coli </it>cell growth and recombinant product formation in chemostat cultivations.</p
Active wetting of epithelial tissues
Development, regeneration and cancer involve drastic transitions in tissue
morphology. In analogy with the behavior of inert fluids, some of these
transitions have been interpreted as wetting transitions. The validity and
scope of this analogy are unclear, however, because the active cellular forces
that drive tissue wetting have been neither measured nor theoretically
accounted for. Here we show that the transition between 2D epithelial
monolayers and 3D spheroidal aggregates can be understood as an active wetting
transition whose physics differs fundamentally from that of passive wetting
phenomena. By combining an active polar fluid model with measurements of
physical forces as a function of tissue size, contractility, cell-cell and
cell-substrate adhesion, and substrate stiffness, we show that the wetting
transition results from the competition between traction forces and contractile
intercellular stresses. This competition defines a new intrinsic lengthscale
that gives rise to a critical size for the wetting transition in tissues, a
striking feature that has no counterpart in classical wetting. Finally, we show
that active shape fluctuations are dynamically amplified during tissue
dewetting. Overall, we conclude that tissue spreading constitutes a prominent
example of active wetting --- a novel physical scenario that may explain
morphological transitions during tissue morphogenesis and tumor progression
Exploring the Universe with Metal-Poor Stars
The early chemical evolution of the Galaxy and the Universe is vital to our
understanding of a host of astrophysical phenomena. Since the most metal-poor
Galactic stars (with metallicities down to [Fe/H]\sim-5.5) are relics from the
high-redshift Universe, they probe the chemical and dynamical conditions of the
Milky Way and the origin and evolution of the elements through nucleosynthesis.
They also provide constraints on the nature of the first stars, their
associated supernovae and initial mass function, and early star and galaxy
formation. The Milky Way's dwarf satellites contain a large fraction (~30%) of
the known most metal-poor stars that have chemical abundances that closely
resemble those of equivalent halo stars. This suggests that chemical evolution
may be universal, at least at early times, and that it is driven by massive,
energetic SNe. Some of these surviving, ultra-faint systems may show the
signature of just one such PopIII star; they may even be surviving first
galaxies. Early analogs of the surviving dwarfs may thus have played an
important role in the assembly of the old Galactic halo whose formation can now
be studied with stellar chemistry. Following the cosmic evolution of small
halos in simulations of structure formation enables tracing the cosmological
origin of the most metal-poor stars in the halo and dwarf galaxies. Together
with future observations and additional modeling, many of these issues,
including the reionization history of the Milky Way, may be constrained this
way. The chapter concludes with an outlook about upcoming observational
challenges and ways forward is to use metal-poor stars to constrain theoretical
studies.Comment: 34 pages, 11 figures. Book chapter to appear in "The First Galaxies -
Theoretical Predictions and Observational Clues", 2012 by Springer, eds. V.
Bromm, B. Mobasher, T. Wiklin
Communication style and exercise compliance in physiotherapy (CONNECT). A cluster randomized controlled trial to test a theory-based intervention to increase chronic low back pain patientsâ adherence to physiotherapistsâ recommendations: study rationale, design, and methods
Physical activity and exercise therapy are among the accepted clinical rehabilitation guidelines and are recommended self-management strategies for chronic low back pain. However, many back pain sufferers do not adhere to their physiotherapistâs recommendations. Poor patient adherence may decrease the effectiveness of advice and home-based rehabilitation exercises. According to self-determination theory, support from health care practitioners can promote patientsâ autonomous motivation and greater long-term behavioral persistence (e.g., adherence to physiotherapistsâ recommendations). The aim of this trial is to assess the effect of an intervention designed to increase physiotherapistsâ autonomy-supportive communication on low back pain patientsâ adherence to physical activity and exercise therapy recommendations. \ud
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This study will be a single-blinded cluster randomized controlled trial. Outpatient physiotherapy centers (N =12) in Dublin, Ireland (populationâ=â1.25 million) will be randomly assigned using a computer-generated algorithm to either the experimental or control arm. Physiotherapists in the experimental arm (two hospitals and four primary care clinics) will attend eight hours of communication skills training. Training will include handouts, workbooks, video examples, role-play, and discussion designed to teach physiotherapists how to communicate in a manner that promotes autonomous patient motivation. Physiotherapists in the waitlist control arm (two hospitals and four primary care clinics) will not receive this training. Participants (Nâ=â292) with chronic low back pain will complete assessments at baseline, as well as 1âweek, 4âweeks, 12âweeks, and 24âweeks after their first physiotherapy appointment. Primary outcomes will include adherence to physiotherapy recommendations, as well as low back pain, function, and well-being. Participants will be blinded to treatment allocation, as they will not be told if their physiotherapist has received the communication skills training. Outcome assessors will also be blinded. \ud
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We will use linear mixed modeling to test between arm differences both in the mean levels and the rates of change of the outcome variables. We will employ structural equation modeling to examine the process of change, including hypothesized mediation effects. \ud
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This trial will be the first to test the effect of a self-determination theory-based communication skills training program for physiotherapists on their low back pain patientsâ adherence to rehabilitation recommendations. Current Controlled Trials ISRCTN63723433\u
Hypothyroidism among military infants born in countries of varied iodine nutrition status
<p>Abstract</p> <p>Background</p> <p>Iodine deficiency is a global problem representing the most common preventable cause of mental retardation. Recently, the impact of subtle deficiencies in iodine intake on children and pregnant women has been questioned. This study was designed to compare hypothyroidism among infants born to US military families in countries of varied iodine nutrition status.</p> <p>Methods</p> <p>A cohort design was used to analyze data from the Department of Defense Birth and Infant Health Registry for infants born in 2000-04 (<it>n </it>= 447,691). Hypothyroidism was defined using ICD-9-CM codes from the first year of life (<it>n </it>= 698). The impact of birth location on hypothyroidism was assessed by comparing rates in Germany, Japan, and US territories with the United States, while controlling for infant gender, plurality, gestational age, maternal age, maternal military status, and military parent's race/ethnicity.</p> <p>Results</p> <p>Hypothyroidism did not vary by birth location with adjusted odds ratios (OR) as follows: Germany (OR 0.82, [95% CI 0.50, 1.35]), Japan (OR 0.67, [95% CI 0.37, 1.22]), and US territories (OR 1.29, [95% CI 0.57, 2.89]). Hypothyroidism was strongly associated with preterm birth (OR 5.44, [95% CI 4.60, 6.42]). Hypothyroidism was also increased among infants with civilian mothers (OR 1.24, [95% CI 1.00, 1.54]), and older mothers, especially ages 40 years and older (OR 2.09, [95% CI 1.33, 3.30]).</p> <p>Conclusions</p> <p>In this study, hypothyroidism in military-dependent infants did not vary by birth location, but was associated with other risk factors, including preterm birth, civilian maternal status, and advanced maternal age.</p
A framework for estimating forest disturbance intensity from successive remotely sensed biomass maps:Moving beyond average biomass loss estimates
This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Background The success of satellites in mapping deforestation has been invaluable for improving our understanding of the impacts and nature of land cover change and carbon balance. However, current satellite approaches struggle to quantify the intensity of forest disturbance, i.e. whether the average rate of biomass loss for a region arises from heavy disturbance focused in a few locations, or the less severe disturbance of a wider area. The ability to distinguish between these, very different, disturbance regimes remains critical for forest managers and ecologists. Results We put forward a framework for describing all intensities of forest disturbance, from deforestation, to widespread low intensity disturbance. By grouping satellite observations into ensembles with a common disturbance regime, the framework is able to mitigate the impacts of poor signal-to-noise ratio that limits current satellite observations. Using an observation system simulation experiment we demonstrate that the framework can be applied to provide estimates of the mean biomass loss rate, as well as distinguish the intensity of the disturbance. The approach is robust despite the large random and systematic errors typical of biomass maps derived from radar. The best accuracies are achieved with ensembles of âĽ1600 pixels (âĽ1 km 2 with 25 by 25 m pixels). Summary The framework we describe provides a novel way to describe and quantify the intensity of forest disturbance, which could help to provide information on the causes of both natural and anthropogenic forest lossâsuch information is vital for effective forest and climate policy formulation.ESANERC National Centre for Earth ObservationNERC CarbonFusion projectMpingo Conservation and Development InitiativeEU Framework 7 I-REDD + projec
Men's preferences for prostate cancer screening: A discrete choice experiment
Background: Screening for prostate cancer (PC) may save lives, but overdiagnosis and overtreatment are serious drawbacks. We aimed to determine men's preferences for PC screening, and to elicit the trade-offs they make. Methods: A discrete choice experiment (DCE) was conducted among a population-based random sample of 1000 elderly men (55-75-years-old). Trade-offs were quantified with a panel latent class model between five PC screening aspects: risk reduction of PC-related death, screening interval, risk of unnecessary biopsies, risk of unnecessary treatments, and out-of-pocket costs. Results: The response rate was 46% (459/1000). Men were willing to trade-off 2.0% (CI: 1.6%-2.4%) or 1.8% (CI: 1.3%-2.3%) risk reduction of PC-related death to decrease their risk of unnecessary treatment or biopsy with 10%, respectively. They were willing to pay \[euro]188 per year (CI: \[euro]141-\[euro]258) to reduce their relative risk of PC-related death with 10%. Preference heterogeneity was substantial, with men with higher educational levels having a lower probability to opt for PC screening than men with lower educational levels. Conclusion: Men were willing to trade-off some risk reduction of PC-related death to be relieved of the burden of biopsies or unnecessary treatments. Increasing knowledge on overdiagnosis and overtreatment, especially for men with lower educational levels, is warranted to prevent unrealistic expectations from PC screening. Š 2013 Cancer Research UK. All rights reserved
Age-Corrected Beta Cell Mass Following Onset of Type 1 Diabetes Mellitus Correlates with Plasma C-Peptide in Humans
The inability to produce insulin endogenously precipitates the clinical symptoms of type 1 diabetes mellitus. However, the dynamic trajectory of beta cell destruction following onset remains unclear. Using model-based inference, the severity of beta cell destruction at onset decreases with age where, on average, a 40% reduction in beta cell mass was sufficient to precipitate clinical symptoms at 20 years of age. While plasma C-peptide provides a surrogate measure of endogenous insulin production post-onset, it is unclear as to whether plasma C-peptide represents changes in beta cell mass or beta cell function. The objective of this paper was to determine the relationship between beta cell mass and endogenous insulin production post-onset.Model-based inference was used to compare direct measures of beta cell mass in 102 patients against contemporary measures of plasma C-peptide obtained from three studies that collectively followed 834 patients post-onset of clinical symptoms. An empirical Bayesian approach was used to establish the level of confidence associated with the model prediction. Age-corrected estimates of beta cell mass that were inferred from a series of landmark pancreatic autopsy studies significantly correlate (p>0.9995) with contemporary measures of plasma C-peptide levels following onset.Given the correlation between beta cell mass and plasma C-peptide following onset, plasma C-peptide may provide a surrogate measure of beta cell mass in humans. The clinical relevance of this study is that therapeutic strategies that provide an increase in plasma C-peptide over the predicted value for an individual may actually improve beta cell mass. The model predictions may establish a standard historical "control" group - a prior in a Bayesian context - for clinical trials
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