Summary 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 t...

Summary 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 lamot...

Fifty-six renal allograft recipients were studied prospectively for 3 months or longer after transplant. The polymerase chain reaction (PCR) was used to screen peripheral blood leucocyte (PBL) specimens for CMV, human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7) DNA (DNAemia) in 67 healthy controls and in serial (fortnightly) PBL specimens from the 56 allograft recipients. None of the healthy controls had detectable CMV DNAemia, although HHV6 and HHV7 DNAemia was found in 7% and 9% of individuals respectively. In contrast, DNAemia due to CMV, HHV6 and HHV7 was found in 50%, 36% and 39% of patients respectively, at some time during the post-transplant period. Of the 28 patients who had CMV DNAemia, eight developed "CMV disease". The risk of progression to "CMV disease" was increased in patients with concurrent DNAemia to all three viruses (relative risk 3.7; 95% CI 1.3-10.5). The relative risk of "CMV disease" for patients with concurrent CMV and HHV7 was also increased (RR = 3.5; 95% CI = 1.1-11.6), while the association between CMV and HHV6 was inconclusive (RR = v2.1; 95% CI = 0.7-6.6). The first 26 patients recruited to the study also had serial serum samples tested for antibody responses to the three viruses. "CMV disease" was associated with rising antibody titres to HHV7 (Fisher's exact test, P = 0.02), and weakly so with HHV6 (P = 0.07). It is concluded that in patients with CMV DNAemia, concurrent infection/reactivation HHV7 (and possibly HHV6) is associated with an increased risk of progression to "CMV disease".

SummaryHaemorrhagic cystitis (HC) is a common and, in its severe form, potentially life-threatening complication of Haematopoietic stem cell transplantation (HSCT) in children. Recent data indicate an important role of BK virus reactivation during the time of maximal post-transplant immune suppression in the pathogenesis of late-onset HC. Treatment of HC is mainly symptomatic and often frustrating. To give clinicians guidance on prevention and treatment options and their backing by scientific evidence, we have systematically assessed the available literature and devised evidence-based guidelines. Our comprehensive review demonstrates that evidence for the most commonly used interventions (such as cidofovir, oestrogen, hyperbaric oxygen, bladder instillation with formalin, alum salts or prostaglandin) is very limited. Some of these interventions also carry significant risks. Higher level evidence exists only for 2-mercaptoethane sodium (MESNA) and hyperhydration as a preventative intervention, and for systemic recombinant Factor VII as a treatment to stop acute haemorrhage. Further high-quality studies are required to establish effective and safe prevention and treatment options for HC.

The aim of this study was to determine if gastroenteric viruses were present on surfaces and equipment in a pediatric primary immunodeficiency unit (PPIU) by environmental sampling using swabs and subsequent nucleic acid extraction and reverse transcriptase PCR assays. A PPIU was chosen, and 11 swabs were taken at the same sites every 2 weeks for 6 months. Nested/heminested PCR assays were used to screen for astroviruses (AsV), noroviruses (NoV), and rotaviruses (RV). AsV, NoV, and RV were detected at multiple swab sites during the study period. NoV was the most frequently detected virus on environmental surfaces; however, RV was detected on 79% and NoV on 50% of swabbing dates during the study period. Toilet taps were the most contaminated sites. Fecal samples from selected patients in the unit were also screened during the study period, and patients excreted AsV, NoV, and RV at times during the study. New cleaning schedules and changes in some of the PPIU sanitary furniture have been suggested as a means of reducing environmental contamination.