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IntroductionAntiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Over the past 20 years, a number of new drugs have been approved for National Health Service (NHS) use on the basis of information from short-term trials that demonstrate efficacy. These trials do not provide information about the longer term outcomes, which inform treatment policy. This trial will assess the long-term clinical and cost-effectiveness of the newer treatment levetiracetam and zonisamide.Methods and analysisThis is a phase IV, multicentre, open-label, randomised, controlled clinical trial comparing new and standard treatments for patients with newly diagnosed epilepsy. Arm A of the trial randomised 990 patients with focal epilepsy to standard AED lamotrigine or new AED levetiracetam or zonisamide. Arm B randomised 520 patients with generalised epilepsy to standard AED sodium valproate or new AED levetiracetam. Patients are recruited from UK NHS outpatient epilepsy, general neurology and paediatric clinics. Included patients are aged 5 years or older with two or more spontaneous seizures requiring AED monotherapy, who are not previously treated with AEDs. Patients are followed up for a minimum of 2 years. The primary outcome is time to 12-month remission from seizures. Secondary outcomes include time to treatment failure (including due to inadequate seizure control or unacceptable adverse reactions); time to first seizure; time to 24-month remission; adverse reactions and quality of life. All primary analyses will be on an intention to treat basis. Separate analyses will be undertaken for each arm. Health economic analysis will be conducted from the perspective of the NHS to assess the cost-effectiveness of each AED.Ethics and disseminationThis trial has been approved by the North West-Liverpool East REC (Ref. 12/NW/0361). The trial team will disseminate the results through scientific meetings, peer-reviewed publications and patient and public involvement.Trial registration numbersEudraCT 2012-001884-64; ISRCTN30294119.

Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. National Institute for Health Research Health Technology Assessment Programme.

Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. National Institute for Health Research Health Technology Assessment programme.

Background SARS-CoV-2 is frequently shed in the stool of patients hospitalised with COVID-19. The extent of faecal shedding of SARS-CoV-2 among individuals in the community, and its potential to contribute to spread of disease, is unknown. Methods In this prospective, observational cohort study among households in Liverpool, UK, participants underwent weekly nasal/throat swabbing to detect SARS-CoV-2 virus, over a 12-week period from enrolment starting July 2020. Participants that tested positive for SARS-CoV-2 were asked to provide a stool sample three and 14 days later. In addition, in October and November 2020, during a period of high community transmission, stool sampling was undertaken to determine the prevalence of SARS-CoV-2 faecal shedding among all study participants. SARS-CoV-2 RNA was detected using Real-Time PCR. Results A total of 434 participants from 176 households were enrolled. Eighteen participants (4.2%: 95% confidence interval [CI] 2.5–6.5%) tested positive for SARS-CoV-2 virus on nasal/throat swabs and of these, 3/17 (18%: 95% CI 4–43%) had SARS-CoV-2 detected in stool. Two of three participants demonstrated ongoing faecal shedding of SARS-CoV-2, without gastrointestinal symptoms, after testing negative for SARS-CoV-2 in respiratory samples. Among 165/434 participants without SARS-CoV-2 infection and who took part in the prevalence study, none had SARS-CoV-2 in stool. There was no demonstrable household transmission of SARS-CoV-2 among households containing a participant with faecal shedding. Conclusions Faecal shedding of SARS-CoV-2 occurred among community participants with confirmed SARS-CoV-2 infection. However, during a period of high community transmission, faecal shedding of SARS-CoV-2 was not detected among participants without SARS-CoV-2 infection. It is unlikely that the faecal-oral route plays a significant role in household and community transmission of SARS-CoV-2.

Objective To investigate the length of time taken to open UK research sites in multicentre clinical trials and to identify reasons for any delays. Design A case study, recording key milestone dates from the time a site receives ethical approval through to opening to recruitment. Delay reasons were prospectively logged by trial staff at a minimum of fortnightly periods using a coding system. Setting SANADII, a phase IV pragmatic trial, managed by the Clinical Trials Research Centre, Liverpool. The trial seeks to work with over 100 National Health Service (NHS) sites to meet its recruitment target of 1510 patients. Outcomes and analysis The primary outcome was time from Multicentre Regional Ethics Committee (MREC) approval to site opening using survival analysis. Where sites took over a specified time to reach milestones (>3 months from MREC to Site Specific Information (SSI) submission, >30 days from SSI validation to local R&D approval, or >30 days from local Research and Development (R&D) approval to opening to recruitment), the longest continuous delay during that milestone was identified. Results The median opening time for participating sites was 9.7 months (IQR 6.2 to Not Reached). SSI submission took 7 months (IQR 4.1–12.3) from ethics approval, R&D approval took 16 days (IQR 5.0–32.0) from SSI validation and site opening took 15 days (IQR 8.5–40.0) following R&D approval. The longest delays before SSI submission resulted from negotiating excess treatment costs, finalising logistics, collecting CVs and ongoing participation discussions. Conclusions While recently imposed targets are reducing the time taken for R&D departments to approve valid applications, the time taken to open UK research sites remains excessive and must be reduced. At present significant public funds are being used inefficiently in order to navigate NHS systems, challenging the resolve of trial teams and the competitiveness of the UK.

IntroductionThe emergence and rapid spread of COVID-19 have caused widespread and catastrophic public health and economic impact, requiring governments to restrict societal activity to reduce the spread of the disease. The role of household transmission in the population spread of SARS-CoV-2, and of host immunity in limiting transmission, is poorly understood. This paper describes a protocol for a prospective observational study of a cohort of households in Liverpool City Region, UK, which addresses the transmission of SARS-CoV-2 between household members and how immunological response to the infection changes over time.Methods and analysisHouseholds in the Liverpool City Region, in which members have not previously tested positive for SARS-CoV-2 with a nucleic acid amplification test, are followed up for an initial period of 12 weeks. Participants are asked to provide weekly self-throat and nasal swabs and record their activity and presence of symptoms. Incidence of infection and household secondary attack rates of COVID-19 are measured. Transmission of SARS-CoV-2 will be investigated against a range of demographic and behavioural variables. Blood and faecal samples are collected at several time points to evaluate immune responses to SARS-CoV-2 infection and prevalence and risk factors for faecal shedding of SARS-CoV-2, respectively.Ethics and disseminationThe study has received approval from the National Health Service Research Ethics Committee; REC Reference: 20/HRA/2297, IRAS Number: 283 464. Results will be disseminated through scientific conferences and peer-reviewed open access publications. A report of the findings will also be shared with participants. The study will quantify the scale and determinants of household transmission of SARS-CoV-2. Additionally, immunological responses before and during the different stages of infection will be analysed, adding to the understanding of the range of immunological response by infection severity.

Cell-cell communication, and specifically epithelial-mesenchymal signalling, is a key factor determining normal tissue development and organisation in hollow organs such as gastrointestinal tract. Mechanisms governing normal epithelial-mesenchymal communication have been studied for many years, but the changes occurring during tissue damage, infection and inflammation, and in cancer, remain unclear. Myofibroblasts are recognised as key mesenchymal cells involved in this communication in health and in disease. Myofibroblasts produce and secrete many proteins responsible for the assembly of extracellular matrix (ECM), tissue organisation and morphogenesis. Initial studies from this laboratory suggested that myofibroblasts might exhibit regulated secretion. The aim of this project was to determine the secretory mechanisms of myofibroblasts from the upper gut of normal and cancer tissues, and to address their significance in cancer. Gastric myofibroblasts were shown to exhibit calcium-dependent secretion of the small ECM protein, Transforming growth factor-β inducible protein or TGFβig-h3, in response to acute stimulation (30 min) with insulin-like growth factor (IGF)s. Inhibitors of protein synthesis (actinomycin D and cycloheximide) and of protein transport from endoplasmic reticulum (ER) to Golgi (brefeldin A) inhibited basal, but not IGF-stimulated secretion, as seen from Western blot analyses of media. These observations support the idea that evoked secretion occurs from a pre-formed pool of vesicles. Myofibroblasts from the upper gut showed differences in their secretory phenotype; specifically normal myofibroblasts from stomach exhibited regulated secretion, but their counterparts from oesophagus did not. Moreover, gastric cancer-associated myofibroblasts (CAMs) from patients with poor survival tend not to exhibit regulated secretion. These findings suggest a role for the tissue microenvironment in determining the secretory phenotype of myofibroblasts. Secretome-wide analysis of myofibroblasts media collected after IGF stimulation revealed that about 85% of the secretome exhibits evoked release. The relevant proteins belonged to different classes including ECM proteins, ligands, binding proteins, carbohydrate-binding proteins, proteases and protease inhibitors. These data indicate that myofibroblasts may contribute to tissue organisation by rapid release of substances involved in re-modelling the tissue microenvironment. The regulated secretory phenotype of myofibroblasts was associated with the expression of the chromogranin-like protein, secretogranin II. Knock-down of secretogranin II inhibited regulated secretion, whereas over-expression in myofibroblasts that lacked regulated released - induced it. Expression of secretogranin II by myofibroblasts coincided with the expression of dense core secretory vesicles that were similar to those found in neuroendocrine cells. This work indicates that there is a neuroendocrine-like secretory phenotype in myofibroblasts, as illustrated by the expression of neuroendocrine cell protein secretogranin II and the presence of regulated secretion. However, not all normal myofibroblasts exhibit the regulated phenotype, and in gastric cancer the phenotype correlates with early stage of disease. These findings may be exploitable both in the development of novel therapies and in understanding cancer progression.

River basin management is at present of great importance as a response of the increased frequency of extreme hydrological events in a changing climate. The emerging need for streamflow control awaits a capable hydrological outcome. Data collection and processing are the essence of a proper representation of the hydrological processes in a watershed. The main objective of this study is to introduce an approach for a watershed spatial variability processing hence determining the parameters for building up a hydrological model. The ArcSWAT geographic information system (GIS) interface for the Soil and Water Assessment Tool is used. Geographic Information System (GIS) is a very successful tool for analyzing spatial relationships between important hydrologic features such as rivers, diversions, drains and monitoring points. The ArcSWAT model is a geodatabases system storing the Soil and Water input information and results. The Soil and Water Assessment Tool (SWAT) is an open source watershed scale, semi-distributed hydrological model. Preprocessing of the initial inputs to the SWAT model via the ArcSWAT GIS interface is presented in this paper: digital elevation model set-up for a selected watershed, soil properties and landcover data processing, integration of the attributed data, determining the basic hydrologic parameters for which SWAT model calculations are performed. Statistical evaluation and analysis of the outputs are also presented together with outlines for their further use.

Flash floods are defined as rapidly developing extreme events caused by heavy or excessive amounts of rainfall. Flash floods usually occur over a relatively small area within six hours or less of the extreme event with quite a rapid streamflow rise and fall. Increased occurrence of flash flood events is expected due to climate change and increase in extreme precipitation events [1]. Flash flood forecasting is still a challenge for hydrologists and water professionals due to the complex nature of the event itself. Besides having sufficient background in hydrological and meteorological forecasting as well as information about local conditions yet an adequate approach for flash flood forecasting is needed. The Flash Flood Guidance System (FFGS) is widely recognized for enhancing the capacity to issue timely and accurate flash flood warnings by providing hydrological and meteorological forecasters with real-time information and products. FFGS is based on global data as well as national hydrometeorological data and analyses. In this paper the use of the Black Sea Middle East Flash Flood Guidance System (BSMEFFGS) products for flash flood forecasting by the hydrologists at the Hydrological Forecasting department at the National Institute of Meteorology and Hydrology (NIMH) in Bulgaria is presented. An overview of the FFGS for Bulgaria with closer attention paid to the Flash Flood Guidance (FFG), Flash Flood Risk (FFR) and the Flash Flood Threat Products is introduced. Two case studies are also presented - a flash flood in the town of Shumen and another one in the area of the village of Popovitsa on September 28th 2015.

Floods are one of the deadliest natural disasters in the world. According to the World Meteorological Organization (WMO), this is a consequence of the increasing frequency of heavy precipitation, changes in upstream land use, and a continuously increasing concentration of population and assets in flood-prone areas [1]. For this reason, flood prevention, and protection are a growing priority these days. Flood hazard mapping is a state-of-the-art tool for decision-makers and stakeholders when it comes to flood protection and Flood Risk Management Plans. The visualization of the various parameters (range, depths, velocities, etc.) of a flood event gives a clear vision for implementing measures that help to protect and restore the natural functions of rivers and floodplains. This article presents the different types of flood hazard maps - with either a single parameter or a combination of several parameters (range, depths, velocities, and combination of flow velocity and flow depth. For this purpose, results obtained from 2D modeling with the software product HEC-RAS were used. The digital terrain model used was provided by Drone and has a resolution of 0.05 cm. Land cover information from CLC 2018 was used to determine the Manning coefficients. According to Art. 146e. of the Water Act (New, SG No. 61/2010) [2], several scenarios should be considered for Bulgaria: low-probability floods, medium-probability floods, and high-probability floods. As a result, a number of maps with different probabilities of flood occurrence and different flood parameters were obtained. These maps were used to analyze and assess potential damage in the different flood scenarios and parameters.