2,002 research outputs found

    Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.

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    This is an updated version of the original Cochrane Review, first published in Issue 1, 2003 and updated in 2015. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenobarbitone are commonly used broad-spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures, and is used in the USA and Europe. Phenobarbitone is no longer considered a first-line treatment because of concerns over associated adverse events, particularly documented behavioural adverse events in children treated with the drug. However, phenobarbitone is still commonly used in low- and middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenobarbitone in individual trials; however, the confidence intervals generated by these studies are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy.To review the time to withdrawal, remission, and first seizure of carbamazepine compared with phenobarbitone when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types).For the latest update, we searched the following databases on 18 August 2016: the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid, from 1946), the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov), and the World Health Organization International Clinical Trials Registry Platform (ICTRP). Previously we also searched SCOPUS (from 1823) as an alternative to Embase, but this is no longer necessary, because randomised controlled trials (RCTs) and quasi-RCTs in Embase are now included in CENTRAL. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field.RCTs in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of carbamazepine monotherapy versus phenobarbitone monotherapy.This was an individual participant data (IPD) review. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'adverse events'. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), with the generic inverse variance method used to obtain the overall pooled HR and 95% CI.IPD were available for 836 participants out of 1455 eligible individuals from six out of 13 trials; 57% of the potential data. For remission outcomes, HR > 1 indicated an advantage for phenobarbitone, and for first seizure and withdrawal outcomes, HR > 1 indicated an advantage for carbamazepine.The main overall results (pooled HR adjusted for seizure type, 95% CI) were HR 1.50 for time to withdrawal of allocated treatment (95% CI 1.15 to 1.95; P = 0.003); HR 0.93 for time to achieve 12-month remission (95% CI 0.72 to 1.20; P = 0.57); HR 0.99 for time to achieve six-month remission (95% CI 0.80 to 1.23; P = 0.95); and HR 0.87 for time to first seizure (95% CI 0.72 to 1.06; P = 0.18). Results suggest an advantage for carbamazepine over phenobarbitone in terms of time to treatment withdrawal and no statistically significant evidence between the drugs for the other outcomes. We found evidence of a statistically significant interaction between treatment effect and seizure type for time to first seizure recurrence (Chi² test for subgroup differences P = 0.03), where phenobarbitone was favoured for partial onset seizures (HR 0.76, 95% CI 0.60 to 0.96; P = 0.02) and carbamazepine was favoured for generalised onset seizures (HR 1.23, 95% CI 0.88 to 1.77; P = 0.27). We found no evidence of an interaction between treatment effect and seizure type for the other outcomes. However, methodological quality of the included studies was variable, with 10 out of the 13 included studies (4 out of 6 studies contributing IPD) judged at high risk of bias for at least one methodological aspect, leading to variable individual study results, and therefore, heterogeneity in the analyses of this review. We conducted sensitivity analyses to examine the impact of poor methodological aspects, where possible.Overall, we found evidence suggestive of an advantage for carbamazepine in terms of drug effectiveness compared with phenobarbitone (retention of the drug in terms of seizure control and adverse events) and evidence suggestive of an association between treatment effect and seizure type for time to first seizure recurrence (phenobarbitone favoured for partial seizures and carbamazepine favoured for generalised seizures). However, this evidence was judged to be of low quality due to poor methodological quality and the potential impact on individual study results (and therefore variability (heterogeneity) present in the analysis within this review), we encourage caution when interpreting the results of this review and do not advocate that the results of this review alone should be used in choosing between carbamazepine and phenobarbitone. We recommend that future trials should be designed to the highest quality possible with considerations for allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results

    Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review.

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    This is an updated version of the original Cochrane review published in Issue 1, 2006 of the Cochrane Database of Systematic Reviews.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment up to 70% of individuals with active epilepsy have the potential to become seizure-free and to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy.The correct choice of first-line antiepileptic therapy for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AEDs for an individual is made using the highest quality evidence regarding the potential benefits and harms of the various treatments. It is also important that the effectiveness and tolerability of AEDs appropriate to given seizure types are compared to one another.Carbamazepine or lamotrigine are first-line recommended treatments for new onset partial seizures and as a first- or second-line treatment for generalised tonic-clonic seizures. Performing a synthesis of the evidence from existing trials will increase the precision of the results for outcomes relating to efficacy and tolerability and may assist in informing a choice between the two drugs.To review the time to withdrawal, remission and first seizure with lamotrigine compared to carbamazepine when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types).The first searches for this review were run in 1997. For the most recent update we searched the Cochrane Epilepsy Group Specialized Register (17 October 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 17 October 2016) and MEDLINE (Ovid, 1946 to 17 October 2016). We imposed no language restrictions. We also contacted pharmaceutical companies and trial investigators.Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures comparing monotherapy with either carbamazepine or lamotrigine.This was an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment and our secondary outcomes were time to first seizure post-randomisation, time to six-month, 12-month and 24-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI.We included 13 studies in this review. Individual participant data were available for 2572 participants out of 3394 eligible individuals from nine out of 13 trials: 78% of the potential data. For remission outcomes, a HR < 1 indicated an advantage for carbamazepine and for first seizure and withdrawal outcomes a HR < 1 indicated an advantage for lamotrigine.The main overall results (pooled HR adjusted for seizure type) were: time to withdrawal of allocated treatment (HR 0.72, 95% CI 0.63 to 0.82), time to first seizure (HR 1.22, 95% CI 1.09 to 1.37) and time to six-month remission (HR 0.84, 95% CI 0.74 to 0.94), showing a significant advantage for lamotrigine compared to carbamazepine for withdrawal but a significant advantage for carbamazepine compared to lamotrigine for first seizure and six-month remission. We found no difference between the drugs for time to 12-month remission (HR 0.91, 95% CI 0.77 to 1.07) or time to 24-month remission (HR 1.00, 95% CI 0.80 to 1.25), however only two trials followed up participants for more than one year so the evidence is limited.The results of this review are applicable mainly to individuals with partial onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures.The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs.The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open-label treatment may have influenced the withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment withdrawal to be moderate for individuals with partial onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with partial onset seizures and moderate for individuals with generalised onset seizures.Lamotrigine was significantly less likely to be withdrawn than carbamazepine but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. A choice between these first-line treatments must be made with careful consideration. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results

    Training a convolutional neural network for real–bogus classification in the ATLAS survey

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    We present a convolutional neural network (CNN) for use in the real–bogus classification of transient detections made by the Asteroid Terrestrial-impact Last Alert System (ATLAS) and subsequent efforts to improve performance since initial development. In transient detection surveys, the number of alerts made outstrips the capacity for human scanning, necessitating the use of machine learning aids to reduce the number of false positives presented to annotators. We take a sample of recently annotated data from each of the three operating ATLAS telescope with 340 000 real (known transients) and 1030 000 bogus detections per model. We retrained the CNN architecture with these data specific to each ATLAS unit, achieving a median false positive rate (FPR) of 0.72 per cent for a 1.00 per cent missed detection rate. Further investigations indicate that if we reduce the input image size it results in increased FPR. Finally architecture adjustments and comparisons to contemporary CNNs indicate that our retrained classifier is providing an optimal FPR. We conclude that the periodic retraining and readjustment of classification models on survey data can yield significant improvements as data drift arising from changes in the optical and detector performance can lead to new features in the model and subsequent deteriorations in performance

    Inhibition in multiclass classification

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    The role of inhibition is investigated in a multiclass support vector machine formalism inspired by the brain structure of insects. The so-called mushroom bodies have a set of output neurons, or classification functions, that compete with each other to encode a particular input. Strongly active output neurons depress or inhibit the remaining outputs without knowing which is correct or incorrect. Accordingly, we propose to use a classification function that embodies unselective inhibition and train it in the large margin classifier framework. Inhibition leads to more robust classifiers in the sense that they perform better on larger areas of appropriate hyperparameters when assessed with leave-one-out strategies. We also show that the classifier with inhibition is a tight bound to probabilistic exponential models and is Bayes consistent for 3-class problems. These properties make this approach useful for data sets with a limited number of labeled examples. For larger data sets, there is no significant comparative advantage to other multiclass SVM approaches

    Inhibition in multiclass classification

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    The role of inhibition is investigated in a multiclass support vector machine formalism inspired by the brain structure of insects. The so-called mushroom bodies have a set of output neurons, or classification functions, that compete with each other to encode a particular input. Strongly active output neurons depress or inhibit the remaining outputs without knowing which is correct or incorrect. Accordingly, we propose to use a classification function that embodies unselective inhibition and train it in the large margin classifier framework. Inhibition leads to more robust classifiers in the sense that they perform better on larger areas of appropriate hyperparameters when assessed with leave-one-out strategies. We also show that the classifier with inhibition is a tight bound to probabilistic exponential models and is Bayes consistent for 3-class problems. These properties make this approach useful for data sets with a limited number of labeled examples. For larger data sets, there is no significant comparative advantage to other multiclass SVM approaches

    Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child (Review).

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    Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and neurodevelopmental impairment. Neurodevelopmental impairment is characterised by either a specific deficit or a constellation of deficits across cognitive, motor and social skills and can be transient or continuous into adulthood. It is of paramount importance that these potential risks are identified, minimised and communicated clearly to women with epilepsy. Objectives To assess the effects of prenatal exposure to commonly prescribed AEDs on neurodevelopmental outcomes in the child and to assess the methodological quality of the evidence. Search methods We searched the Cochrane Epilepsy Group Specialized Register (May 2014), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 4), MEDLINE (via Ovid) (1946 to May 2014), EMBASE (May 2014), Pharmline (May 2014) and Reprotox (May 2014). No language restrictions were imposed. Conference abstracts from the last five years were reviewed along with reference lists from the included studies. Selection criteria Prospective cohort controlled studies, cohort studies set within pregnancy registers and randomised controlled trials were selected for inclusion. Participants were women with epilepsy taking AED treatment; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy. Data collection and analysis Three authors (RB, JW and JG) independently selected studies for inclusion. Data extraction and risk of bias assessments were completed by five authors (RB, JW, AS, NA, AJM). The primary outcome was global cognitive functioning. Secondary outcomes included deficits in specific cognitive domains or prevalence of neurodevelopmental disorders. Due to substantial variation in study design and outcome reporting only limited data synthesis was possible. Main results Twenty‐two prospective cohort studies were included and six registry based studies. Study quality varied. More recent studies tended to be larger and to report individual AED outcomes from blinded assessments, which indicate improved methodological quality.The developmental quotient (DQ) was lower in children exposed to carbamazepine (CBZ) (n = 50) than in children born to women without epilepsy (n = 79); mean difference (MD) of ‐5.58 (95% confidence interval (CI) ‐10.83 to ‐0.34, P = 0.04). The DQ of children exposed to CBZ (n = 163) was also lower compared to children of women with untreated epilepsy (n = 58) (MD ‐7.22, 95% CI ‐12.76 to ‐ 1.67, P = 0.01). Further analysis using a random‐effects model indicated that these results were due to variability within the studies and that there was no significant association with CBZ. The intelligence quotient (IQ) of older children exposed to CBZ (n = 150) was not lower than that of children born to women without epilepsy (n = 552) (MD ‐0.03, 95% CI ‐3.08 to 3.01, P = 0.98). Similarly, children exposed to CBZ (n = 163) were not poorer in terms of IQ in comparison to the children of women with untreated epilepsy (n = 87) (MD 1.84, 95% CI ‐2.13 to 5.80, P = 0.36). The DQ in children exposed to sodium valproate (VPA) (n = 123) was lower than the DQ in children of women with untreated epilepsy (n = 58) (MD ‐8.72, 95% ‐14.31 to ‐3.14, P = 0.002). The IQ of children exposed to VPA (n = 76) was lower than for children born to women without epilepsy (n = 552) (MD ‐8.94, 95% CI ‐11.96 to ‐5.92, P < 0.00001). Children exposed to VPA (n = 89) also had lower IQ than children born to women with untreated epilepsy (n = 87) (MD ‐8.17, 95% CI ‐12.80 to ‐3.55, P = 0.0005). In terms of drug comparisons, in younger children there was no significant difference in the DQ of children exposed to CBZ (n = 210) versus VPA (n=160) (MD 4.16, 95% CI ‐0.21 to 8.54, P = 0.06). However, the IQ of children exposed to VPA (n = 112) was significantly lower than for those exposed to CBZ (n = 191) (MD 8.69, 95% CI 5.51 to 11.87, P < 0.00001). The IQ of children exposed to CBZ (n = 78) versus lamotrigine (LTG) (n = 84) was not significantly different (MD ‐1.62, 95% CI ‐5.44 to 2.21, P = 0.41). There was no significant difference in the DQ of children exposed to CBZ (n = 172) versus phenytoin (PHT) (n = 87) (MD 3.02, 95% CI ‐2.41 to 8.46, P = 0.28). The IQ abilities of children exposed to CBZ (n = 75) were not different from the abilities of children exposed to PHT (n = 45) (MD ‐3.30, 95% CI ‐7.91 to 1.30, P = 0.16). IQ was significantly lower for children exposed to VPA (n = 74) versus LTG (n = 84) (MD ‐10.80, 95% CI ‐14.42 to ‐7.17, P < 0.00001). DQ was higher in children exposed to PHT (n = 80) versus VPA (n = 108) (MD 7.04, 95% CI 0.44 to 13.65, P = 0.04). Similarly IQ was higher in children exposed to PHT (n = 45) versus VPA (n = 61) (MD 9.25, 95% CI 4.78 to 13.72, P < 0.0001). A dose effect for VPA was reported in six studies, with higher doses (800 to 1000 mg daily or above) associated with a poorer cognitive outcome in the child. We identified no convincing evidence of a dose effect for CBZ, PHT or LTG. Studies not included in the meta‐analysis were reported narratively, the majority of which supported the findings of the meta‐analyses. Authors' conclusions The most important finding is the reduction in IQ in the VPA exposed group, which are sufficient to affect education and occupational outcomes in later life. However, for some women VPA is the most effective drug at controlling seizures. Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre‐conceptual counselling. We have insufficient data about newer AEDs, some of which are commonly prescribed, and further research is required. Most women with epilepsy should continue their medication during pregnancy as uncontrolled seizures also carries a maternal risk

    A Miniature Fibre-Optic Raman Probe Fabricated by Ultrafast Laser-Assisted Etching

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    Optical biopsy describes a range of medical procedures in which light is used to investigate disease in the body, often in hard-to-reach regions via optical fibres. Optical biopsies can reveal a multitude of diagnostic information to aid therapeutic diagnosis and treatment with higher specificity and shorter delay than traditional surgical techniques. One specific type of optical biopsy relies on Raman spectroscopy to differentiate tissue types at the molecular level and has been used successfully to stage cancer. However, complex micro-optical systems are usually needed at the distal end to optimise the signal-to-noise properties of the Raman signal collected. Manufacturing these devices, particularly in a way suitable for large scale adoption, remains a critical challenge. In this paper, we describe a novel fibre-fed micro-optic system designed for efficient signal delivery and collection during a Raman spectroscopy-based optical biopsy. Crucially, we fabricate the device using a direct-laser-writing technique known as ultrafast laser-assisted etching which is scalable and allows components to be aligned passively. The Raman probe has a sub-millimetre diameter and offers confocal signal collection with 71.3% &plusmn; 1.5% collection efficiency over a 0.8 numerical aperture. Proof of concept spectral measurements were performed on mouse intestinal tissue and compared with results obtained using a commercial Raman microscope

    Emissions of trace gases from Australian temperate forest fires: emission factors and dependence on modified combustion efficiency

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    We characterised trace gas emissions from Australian temperate forest fires through a mixture of open-path Fourier transform infrared (OP-FTIR) measurements and selective ion flow tube mass spectrometry (SIFT-MS) and White cell FTIR analysis of grab samples. We report emission factors for a total of 25 trace gas species measured in smoke from nine prescribed fires. We find significant dependence on modified combustion efficiency (MCE) for some species, although regional differences indicate that the use of MCE as a proxy may be limited. We also find that the fire-integrated MCE values derived from our in situ on-the-ground open-path measurements are not significantly different from those reported for airborne measurements of smoke from fires in the same ecosystem. We then compare our average emission factors to those measured for temperate forest fires elsewhere (North America) and for fires in another dominant Australian ecosystem (savanna) and find significant differences in both cases. Indeed, we find that although the emission factors of some species agree within 20 %, including those of hydrogen cyanide, ethene, methanol, formaldehyde and 1,3-butadiene, others, such as acetic acid, ethanol, monoterpenes, ammonia, acetonitrile and pyrrole, differ by a factor of 2 or more. This indicates that the use of ecosystem-specific emission factors is warranted for applications involving emissions from Australian forest fires
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