The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: 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. Methods: 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). Findings: 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. Interpretation: 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. Funding: National Institute for Health Research Health Technology Assessment programme

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: 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. Methods: 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). Findings: 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. Interpretation: 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. Funding: National Institute for Health Research Health Technology Assessment Programme

Global investments in pandemic preparedness and COVID-19: development assistance and domestic spending on health between 1990 and 2026

Background The COVID-19 pandemic highlighted gaps in health surveillance systems, disease prevention, and treatment globally. Among the many factors that might have led to these gaps is the issue of the financing of national health systems, especially in low-income and middle-income countries (LMICs), as well as a robust global system for pandemic preparedness. We aimed to provide a comparative assessment of global health spending at the onset of the pandemic; characterise the amount of development assistance for pandemic preparedness and response disbursed in the first 2 years of the COVID-19 pandemic; and examine expectations for future health spending and put into context the expected need for investment in pandemic preparedness. Methods In this analysis of global health spending between 1990 and 2021, and prediction from 2021 to 2026, we estimated four sources of health spending: development assistance for health (DAH), government spending, out-of-pocket spending, and prepaid private spending across 204 countries and territories. We used the Organisation for Economic Co-operation and Development (OECD)'s Creditor Reporting System (CRS) and the WHO Global Health Expenditure Database (GHED) to estimate spending. We estimated development assistance for general health, COVID-19 response, and pandemic preparedness and response using a keyword search. Health spending estimates were combined with estimates of resources needed for pandemic prevention and preparedness to analyse future health spending patterns, relative to need. Findings In 2019, at the onset of the COVID-19 pandemic, US$9·2 trillion (95$7·3 trillion (95% UI 7·2–7·4) in 2019; 293·7 times the $24·8 billion (95$43·1 billion in development assistance was provided to maintain or improve health. The pandemic led to an unprecedented increase in development assistance targeted towards health; in 2020 and 2021, $1·8 billion in DAH contributions was provided towards pandemic preparedness in LMICs, and$37·8 billion was provided for the health-related COVID-19 response. Although the support for pandemic preparedness is 12·2% of the recommended target by the High-Level Independent Panel (HLIP), the support provided for the health-related COVID-19 response is 252·2% of the recommended target. Additionally, projected spending estimates suggest that between 2022 and 2026, governments in 17 (95% UI 11–21) of the 137 LMICs will observe an increase in national government health spending equivalent to an addition of 1% of GDP, as recommended by the HLIP. Interpretation There was an unprecedented scale-up in DAH in 2020 and 2021. We have a unique opportunity at this time to sustain funding for crucial global health functions, including pandemic preparedness. However, historical patterns of underfunding of pandemic preparedness suggest that deliberate effort must be made to ensure funding is maintained

Ecology of Dorymyrmex flavus McCook (Hymenoptera: Formicidae) in central Texas, including aspects of competition with Solenopsis invicta Buren (Hymenoptera: Formicidae)

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references: p.55-58.Issued also on microfiche from Lange Micrographics.Dorymyrmex species, commonly known as "pyramid ants," are found throughout the United States, but are most common in the South. They occur in open areas, without a closed canopy overhead, and prefer to nest in sandy soils. Dorymyrmex flavus McCook is one of six species found in Texas. Similar to the other Dorymyrmex species, it is an opportunistic omnivore. It feeds on honeydew and other arthropods, both by hunting and also scavenging. The colony sizes in central Texas are much smaller than those of the same species found in Florida, with numbers of less than I 000 workers in late summer and early fall. No size castes exist among workers, thus this species is monomorphic. This species swarms from the summer months well into the fall season, as indicated by the presence of winged males. The nests occur in open areas and sandy substrates, such as Zulch Fine Sandy Loam. Colonies are polydomous, and build the nest to a depth of a least 61 cm. Despite possessing no sting and existing in small colonies, D. flavor continues to thrive in,Yolenopsis invicta Buren infested areas. This is accomplished by a combination of several factors. First, D..flavus is an effective defender of the nest, in which it uses its mandibles to kill invaders. Second, it may possess an ability to seal off tunnels and escape, in the event of an invasion. Third, the fact that D. flavus occupies soils that are not well suited to S. invicta keeps the colonies somewhat spatially separated, limiting the stimulus for a large scale invasion. Fourth, D. flavus colonies often occur in clumps, increasing the numbers to defend a territory. Lastly, D. flavus exhibits extremely aggressive behavior toward newly mated S. invicta queens, which prevents new ,S. invicta colonies from forming nearby, thereby lowering the threat of competition

Influence of Temperature on Rate of Uptake and Subsequent Horizontal Transfer of [\u3csup\u3e14\u3c/sup\u3eC]Fipronil by Eastern Subterranean Termites (Isoptera: Rhinotermitidae)

The effect of temperature on [14C]fipronil uptake and transfer from donor (D) to recipient (R) Reticulitermes flavipes (Kollar) (Isoptera: Rhinotermitidae) workers was evaluated. Test chambers used in the fipronil uptake study were constructed from petri dishes containing autoclaved soil treated with 1 ppm [14C]fipronil (1.14 μCi of total radioactivity per petri dish), distilled water, and R. flavipes workers. Test chambers were held in environmental growth chambers preset at 12, 17, 22, 27, and 32°C. For the fipronil transfer study, donor termites stained with Nile blue-A were exposed to soil treated with 1 ppm [14C]fipronil for 2 h. Donors were then combined with unexposed recipient termite workers at either 1D:5R, 1D:10R, or 1D:20R ratios. Test chambers consisted of a nest and feeding chamber connected by a piece of polyethylene tube and held in growth chambers at 12, 17, 22, 27, and 32°C. Worker termites were sampled over time and the amount of [14C]fipronil present was measured by scintillation counting. Some degree of uptake and transfer occurred at all temperatures and ratios in this study. The highest level of uptake occurred by termites held at 22-32°C, followed decreasingly by 17 and 12°C. Maximum transfer of [14C]fipronil occurred at the higher ratios (1:5 \u3e 1:10 \u3e 1:20) of donors to recipients. Data presented in this study suggest that temperature is one of the key factors affecting the rate of uptake and subsequent horizontal transfer of [14C]fipronil in subterranean termites

A comparison of amrinone with sodium nitroprusside for control of hemodynamics during infrarenal abdominal aortic surgery

The control of hemodynamic changes during surgical resection of abdominal aortic aneurysms (AAA) remains a challenge to anesthesiologists. In the past, hypertensive episodes have been treated with sodium nitroprusside (SNP). However, amrinone may provide some benefits when compared with SNP because of its positive inotropic and vasodilatory properties. Therefore, the purpose of this study was to compare amrinone with SNP for hemodynamic control during AAA surgery. This study was a prospective, randomized investigation. This study was performed at a single university hospital. This study included 20 patients undergoing AAA resection. After institutional review board approval, participants were randomized to receive either SNP (group N = 10) or amrinone (group A = 10). Both agents were started 10 minutes before aortic cross-clamping and discontinued 10 minutes before unclamping. Anesthesia was induced with thiopental or etomidate and maintained with oxygen, nitrous oxide, isoflurane, fentanyl, and vecuronium. Hemodynamic measurements included heart rate, systolic and diastolic blood pressure, cardiac output, systolic and diastolic pulmonary artery pressure, pulmonary capillary wedge pressure, central venous pressure, mixed venous oxygen saturation, electrocardiogram, and ST-T wave trend analysis. Demographic and clinical characteristics for the two groups were similar. Mixed venous oxygen saturation was significantly lower ( p < 0.05) in group N immediately after unclamping. There were no differences between groups for the other measurements studied. There were no episodes of myocardial ischemia in either group. This study demonstrates that amrinone provides equivalent hemodynamic control to SNP during abdominal aortic aneurysm surgery because it allows moderate reductions in blood pressure without affecting other hemodynamic measurements. Further studies are needed to assess whether patients with poor preoperative left ventricular function would benefit from amrinone management during AAA resection

CCDC 967582: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures