2,604 research outputs found
How do paediatricians use and monitor antithyroid drugs in the UK? A clinician survey
Objective
We aimed to document current practice in the medical management of paediatric hyperthyroidism in the UK and compare to international recommendations.
Design
A 27âquestion online survey distributed via an electronic newsletter in August 2018.
Participants
Responses from 48 members (11%) of the British Society for Paediatric Endocrinology and Diabetes.
Measurements
Information about antithyroid drug (ATD) preference, treatment duration, monitoring of full blood count (FBC), management of neutropaenia, agranulocytosis screening and patient education.
Results
Carbimazole is favoured by 98% of respondents and a âdose titrationâ regimen preferred over âblock and replaceâ (65% vs 29%). TRAbs (thyroidâstimulating hormone receptor antibodies) are used for diagnostic purposes by 85% and by 33% to look for evidence of disease remission. The majority (81%) treat for a minimum of 2 years before considering a trial off ATD. All respondents reported that they âalways/usuallyâ warn their patients about the risk of agranulocytosis before starting ATD, but written information is ârarely/neverâ provided by 63%. Sore throat (98%) and fever (92%) are the most commonly cited symptoms used to alert a patient to possible agranulocytosis. FBC is measured prior to treatment by 65% and measured periodically during treatment by 70%.
Conclusions
The management of paediatric hyperthyroidism with ATDs in the UK is not consistent with all international recommendations because a block and replace ATD regimen remains widely used. TRAbs are utilized at presentation, but underused for detecting disease remission. National consensus guidelines and written patient information may refine the management of paediatric patients on ATDs
Breast cancer stem cell markers â the rocky road to clinical applications
Lately, understanding the role of cancer stem cells in tumor initiation and progression became a major focus in stem cell biology and in cancer research. Considerable efforts, such as the recent studies by Honeth and colleagues, published in the June issue of Breast Cancer Research, are directed towards developing clinical applications of the cancer stem cell concepts. This work shows that the previously described CD44+CD24- stem cell phenotype is associated with basal-type breast cancers in human patients, in particular BRCA1 inherited cancers, but does not correlate with clinical outcome. These very interesting findings caution that the success of our efforts in translating cancer stem cell research into clinical practice depends on how thorough and rigorous we are at characterizing these cells
Travelling on Graphs with Small Highway Dimension
We study the Travelling Salesperson (TSP) and the Steiner Tree problem (STP)
in graphs of low highway dimension. This graph parameter was introduced by
Abraham et al. [SODA 2010] as a model for transportation networks, on which TSP
and STP naturally occur for various applications in logistics. It was
previously shown [Feldmann et al. ICALP 2015] that these problems admit a
quasi-polynomial time approximation scheme (QPTAS) on graphs of constant
highway dimension. We demonstrate that a significant improvement is possible in
the special case when the highway dimension is 1, for which we present a
fully-polynomial time approximation scheme (FPTAS). We also prove that STP is
weakly NP-hard for these restricted graphs. For TSP we show NP-hardness for
graphs of highway dimension 6, which answers an open problem posed in [Feldmann
et al. ICALP 2015]
Degenerate fermion gas heating by hole creation
Loss processes that remove particles from an atom trap leave holes behind in
the single particle distribution if the trapped gas is a degenerate fermion
system. The appearance of holes increases the temperature and we show that the
heating is (i) significant if the initial temperature is well below the Fermi
temperature , and (ii) increases the temperature to
after half of the system's lifetime, regardless of the initial temperature. The
hole heating has important consequences for the prospect of observing
Cooper-pairing in atom traps.Comment: to be published in PR
Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes
<p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p>
<p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p>
<p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p>
Involvement of Hypoxia-Inducible Factor-1 in the Inflammatory Responses of Human LAD2 Mast Cells and Basophils
We recently showed that hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the pro-allergic functions of human basophils by transcriptional control of energy metabolism via glycolysis as well as directly triggering expression of the angiogenic cytokine vascular endothelium growth factor (VEGF). Here, we investigated HIF-1 involvement in controlling the synthesis of angiogenic and inflammatory cytokines from various human effector cells stimulated by IgE-dependent or innate immune triggers. Purified primary human basophils, LAD2 human mast cells and THP-1 human myeloid cells were used for investigations of FcΔRI and Toll-like receptor (TLR) ligand-induced responses. In contrast to basophils, LAD2 mast cells expressed background levels of HIF-1α, which was largely independent of the effects of stem cell factor (SCF). Both mast cells and basophils expressed TLR2 and 4, albeit weakly compared to THP-1 cells. Cytokine production in mast cells following TLR ligand stimulation was markedly reduced by HIF-1α knockdown in LAD2 mast cells. In contrast, although HIF-1 is involved in IgE-mediated IL-4 secretion from basophils, it is not clearly induced by peptidoglycan (PGN). HIF-1α accumulation is critical for sustaining human allergic effector cell survival and function. This transcription complex facilitates generation of both pro-angiogenic and inflammatory cytokines in mast cells but has a differential role in basophil stimulation comparing IgE-dependent triggering with innate immune stimuli
Trial Protocol: Randomised controlled trial of the effects of very low calorie diet, modest dietary restriction, and sequential behavioural programme on hunger, urges to smoke, abstinence and weight gain in overweight smokers stopping smoking
Background\ud
Weight gain accompanies smoking cessation, but dieting during quitting is controversial as hunger may increase urges to smoke. This is a feasibility trial for the investigation of a very low calorie diet (VLCD), individual modest energy restriction, and usual advice on hunger, ketosis, urges to smoke, abstinence and weight gain in overweight smokers trying to quit. \ud
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Methods\ud
This is a 3 armed, unblinded, randomized controlled trial in overweight (BMI > 25 kg/), daily smokers (CO > 10 ppm); with at least 30 participants in each group. Each group receives identical behavioural support and NRT patches (25 mg(8 weeks),15 mg(2 weeks),10 mg(2 weeks)). The VLCD group receive a 429-559 kcal/day liquid formula beginning 1 week before quitting and continuing for 4 weeks afterwards. The modest energy restricted group (termed individual dietary and activity planning(IDAP)) engage in goal-setting and receive an energy prescription based on individual basal metabolic rate(BMR) aiming for daily reduction of 600 kcal. The control group receive usual dietary advice that accompanies smoking cessation i.e. avoiding feeling hungry but eating healthy snacks. After this, the VLCD participants receive IDAP to provide support for changing eating habits in the longer term; the IDAP group continues receiving this support. The control group receive IDAP 8 weeks after quitting. This allows us to compare IDAP following a successful quit attempt with dieting concurrently during quitting. It also aims to prevent attrition in the unblinded, control group by meeting their need for weight management. Follow-up occurs at 6 and 12 months. \ud
\ud
Outcome measures include participant acceptability, measured qualitatively by semi-structured interviewing and quantitatively by recruitment and attrition rates. Feasibility of running the trial within primary care is measured by interview and questionnaire of the treatment providers. Adherence to the VLCD is verified by the presence of urinary ketones measured weekly. Daily urges to smoke, hunger and withdrawal are measured using the Mood and Physical Symptoms Scale-Combined (MPSS-C) and a Hunger Craving Score (HCS). 24 hour, 7 day point prevalence and 4-week prolonged abstinence (Russell Standard) is confirmed by CO < 10 ppm. Weight, waist and hip circumference and percentage body fat are measured at each visit. \ud
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Trial Registration\ud
Current controlled trials ISRCTN83865809\ud
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A critical evaluation of network and pathway based classifiers for outcome prediction in breast cancer
Recently, several classifiers that combine primary tumor data, like gene
expression data, and secondary data sources, such as protein-protein
interaction networks, have been proposed for predicting outcome in breast
cancer. In these approaches, new composite features are typically constructed
by aggregating the expression levels of several genes. The secondary data
sources are employed to guide this aggregation. Although many studies claim
that these approaches improve classification performance over single gene
classifiers, the gain in performance is difficult to assess. This stems mainly
from the fact that different breast cancer data sets and validation procedures
are employed to assess the performance. Here we address these issues by
employing a large cohort of six breast cancer data sets as benchmark set and by
performing an unbiased evaluation of the classification accuracies of the
different approaches. Contrary to previous claims, we find that composite
feature classifiers do not outperform simple single gene classifiers. We
investigate the effect of (1) the number of selected features; (2) the specific
gene set from which features are selected; (3) the size of the training set and
(4) the heterogeneity of the data set on the performance of composite feature
and single gene classifiers. Strikingly, we find that randomization of
secondary data sources, which destroys all biological information in these
sources, does not result in a deterioration in performance of composite feature
classifiers. Finally, we show that when a proper correction for gene set size
is performed, the stability of single gene sets is similar to the stability of
composite feature sets. Based on these results there is currently no reason to
prefer prognostic classifiers based on composite features over single gene
classifiers for predicting outcome in breast cancer
Cloud impacts on photochemistry: Building a climatology of photolysis rates from the Atmospheric Tomography mission
Abstract. Measurements from actinic flux spectroradiometers on board the
NASA DC-8 during the Atmospheric Tomography (ATom) mission provide an
extensive set of statistics on how clouds alter photolysis rates (J values)
throughout the remote Pacific and Atlantic Ocean basins. J values control
tropospheric ozone and methane abundances, and thus clouds have been included
for more than three decades in tropospheric chemistry modeling. ATom made
four profiling circumnavigations of the troposphere capturing each of the
seasons during 2016â2018. This work examines J values from the Pacific
Ocean flights of the first deployment, but publishes the complete Atom-1 data
set (29Â July to 23Â August 2016). We compare the observed J values (every 3âs along flight track) with those calculated by nine global
chemistryâclimate/transport models (globally gridded, hourly, for a
mid-August day). To compare these disparate data sets, we build a
commensurate statistical picture of the impact of clouds on J values using
the ratio of J-cloudy (standard, sometimes cloudy conditions) to J-clear
(artificially cleared of clouds). The range of modeled cloud effects is
inconsistently large but they fall into two distinct classes: (1)Â models with
large cloud effects showing mostly enhanced J values aloft and or
diminished at the surface and (2)Â models with small effects having nearly
clear-sky J values much of the time. The ATom-1 measurements generally
favor large cloud effects but are not precise or robust enough to point out
the best cloud-modeling approach. The models here have resolutions of 50â200âkm
and thus reduce the occurrence of clear sky when averaging over grid
cells. In situ measurements also average scattered sunlight over a mixed
cloud field, but only out to scales of tens of kilometers. A primary uncertainty
remains in the role of clouds in chemistry, in particular, how models average
over cloud fields, and how such averages can simulate measurements.
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