Does in utero exposure of antiepileptic drugs lead to failure to reach full cognitive potential?

AbstractA clinical scenario of a young female on 800mg of sodium valproate (VPA) who has recently failed lamotrigine (LTG) and levetiracetam (LEV) and who is currently planning a pregnancy is presented. Currently available data pertaining to the longer-term development of children exposed to antiepileptic drugs (AEDs) are reviewed along with considerations around the methodology and interpretation of such research. There is an accumulation of data highlighting significant risks associated with prenatal exposed to VPA, with the level of risk being mediated by dose. The majority of published evidence does not find a significant risk associated with carbamazepine (CBZ) exposure in utero for global cognitive abilities however the evidence for more specific cognitive skills are unclear. Limited data indicate that LTG may be a preferred treatment to VPA in terms of foetal outcome but further evidence is required. Too little data pertaining to LEV exposure is available and a lack of evidence regarding risk of this and other new AEDs should not be interpreted as evidence of safety

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer.

BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P \u3c .05), with borderline significances achieved in the other two (P \u3c .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients

Scalable Open-Vote Network on Ethereum

McCorry et al. (Financial Cryptography 2017) presented the first implementation of a decentralized self-tallying voting protocol on Ethereum. However, their implementation did not scale beyond 40 voters since all the computations were performed on the smart contract. In this paper, we tackle this problem by delegating the bulk computations to an off-chain untrusted administrator in a verifiable manner. Specifically, the administrator tallies the votes off-chain and publishes a Merkle tree that encodes the tallying computation trace. Then, the administrator submits the Merkle tree root and the tally result to the smart contract. Subsequently, the smart contract transits to an intermediate phase where at least a single honest voter can contend the administrator\u27s claimed result if it was not computed correctly. Then, in the worst case, the smart contract verifies the dispute at the cost of an elliptic curve point addition and scalar multiplication, and two Merkle proofs of membership which are logarithmic in the number of voters. This allows our protocol to achieve higher scalability without sacrificing the public verifiability or voters\u27 privacy. To assess our protocol, we implemented an open-source prototype on Ethereum and carried out multiple experiments for different numbers of voters. The results of our implementation confirm the scalability and efficiency of our proposed solution which does not exceed the current block gas limit for any practical number of voters

Quality indicators for Palliative Day Services: A modified Delphi study

BACKGROUND: The goal of Palliative Day Services is to provide holistic care that contributes to the quality of life of people with life threatening-illness and their families. Quality indicators provide a means by which to describe, monitor and evaluate the quality of Palliative Day Services provision, and act as a starting point for quality improvement. However, currently, there are no published quality indicators for Palliative Day Services. AIM: To develop and provide the first set of quality indicators that describe and evaluate the quality of Palliative Day Services. DESIGN AND SETTING: A modified Delphi technique was used to combine best available research evidence derived from a systematic scoping review with multi-disciplinary expert appraisal of the appropriateness and feasibility of candidate indicators. The resulting indicators were compiled into ‘toolkit’, and tested in five UK Palliative Day Service settings. RESULTS: A panel of experts independently reviewed evidence summaries for 182 candidate indicators and provided ratings on appropriateness, followed by a panel discussion and further independent ratings of appropriateness, feasibility, and necessity. This exercise resulted in the identification of 30 indicators which were used in practice testing. The final indicator set comprised 7 structural indicators, 21 process indicators, and 2 outcome indicators. CONCLUSIONS: The indicators fulfil a previously unmet need among Palliative Day Service providers by delivering an appropriate and feasible means to assess, review, and communicate the quality of care, and to identify areas for quality improvement

A statistical comparison of spatio-temporal surface moisture patterns beneath a semi-natural grassland and permanent pasture:From drought to saturation

Some 60% of the agricultural land in the UK is grassland. This is mostly located in the wetter uplands of the west and north, with the majority intensively managed as permanent pasture. Despite its extent, there is a lack of knowledge regarding how agricultural practices have altered the hydrological behaviour of the underlying soils relative to the adjacent moorland covered by semi‐natural grassland. Near‐surface soil moisture content is an expression of the changes that have taken place and is critical in the generation of flood‐producing overland‐flows. This study aims to develop a pioneering paired‐plot approach, producing 1536 moisture measurements at each of the monitoring dates throughout the studied year, that were subsequently analysed by a comparison of frequency distributions, visual‐cum‐geostatistical investigation of spatial patterns and mixed‐effects regression modelling. The analysis demonstrated that the practices taking place in the pasture (ploughing, re‐seeding and drainage) reduced the natural diversity in moisture patterns. Compared to adjacent moorland, the topsoil dried much faster in spring with the effects requiring offset with moisture from slurry applications in summer. With the onset of autumn rains, these applications then made the topsoil wetter than the moorland, heightening the likelihood of flood‐producing overland‐flow. During the sampling within one such storm‐event, the adjacent moorland was almost as wet as the pasture with both visibly generating overland‐flow. These contrasts in soil moisture were statistically significant throughout. Further, they highlight the need to scale‐up the monitoring with numerous plot‐pairs to see if the observed highly dynamic, contrasting behaviour is present at the landscape‐scale. Such research is fundamental to designing appropriate agricultural interventions to deliver sustainable sward production for livestock or methods of mitigating overland‐flow incidence that would otherwise heighten flood‐risk or threaten water‐quality in rivers

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. METHODS: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. FINDINGS: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. INTERPRETATION: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. FUNDING: National Institute for Health Research, Health Technology Assessment programme

Activation of Fluoride Anion as Nucleophile in Water with Data-Guided Surfactant Selection

A principal component surfactant_map was developed for 91 commonly accessible surfactants for use in surfactant-enabled organic reactions in water, an important approach for sustainable chemical processes. This map was built using 22 experimental and theoretical descriptors relevant to the physicochemical nature of these surfactant-enabled reactions, and advanced principal component analysis algorithms. It is comprised of all classes of surfactants, i.e. cationic, anionic, zwitterionic and neutral surfactants, including designer surfactants. The value of this surfactant_map was demonstrated in activating simple inorganic fluoride salts as effective nucleophiles in water, with the right surfactant. This led to the rapid development (screening 13-15 surfactants) of two fluorination reactions for β-bromosulfides and sulfonyl chlorides in water. The latter was demonstrated in generating a sulfonyl fluoride with sufficient purity for direct use in label-ling of chymotrypsin, under physiological conditions