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The 2013 Breast Cancer Campaign gap analysis established breast cancer research priorities without a specific focus on surgical research or the role of surgeons on breast cancer research. This Review aims to identify opportunities and priorities for research in breast surgery to complement the 2013 gap analysis. To identify these goals, research-active breast surgeons met and identified areas for breast surgery research that mapped to the patient pathway. Areas included diagnosis, neoadjuvant treatment, surgery, adjuvant therapy, and attention to special groups (eg, those receiving risk-reducing surgery). Section leads were identified based on research interests, with invited input from experts in specific areas, supported by consultation with members of the Association of Breast Surgery and Independent Cancer Patients' Voice groups. The document was iteratively modified until participants were satisfied that key priorities for surgical research were clear. Key research gaps included issues surrounding overdiagnosis and treatment; optimising treatment options and their selection for neoadjuvant therapies and subsequent surgery; reducing rates of re-operations for breast-conserving surgery; generating evidence for clinical effectiveness and cost-effectiveness of breast reconstruction, and mechanisms for assessing novel interventions; establishing optimal axillary management, especially post-neoadjuvant treatment; and defining and standardising indications for risk-reducing surgery. We propose strategies for resolving these knowledge gaps. Surgeons are ideally placed for a central role in breast cancer research and should foster a culture of engagement and participation in research to benefit patients and health-care systems. Development of infrastructure and surgical research capacity, together with appropriate allocation of research funding, is needed to successfully address the key clinical and translational research gaps that are highlighted in this Review within the next two decades.

SUMMARY POINTS Early prescription of appropriate antibiotics reduces the rate of breast abscess development Refer to hospital all patients whose infection does not settle rapidly after one course of appropriate antibiotics Use ultrasound routinely in patients referred with a suspected abscess to see whether pus is present Breast abscesses can usually be treated in the outpatients department by repeated aspiration or mini-incision and drainage under local anaesthesia Patients whose inflammatory changes do not settle after a course of antibiotics may have inflammatory breast cancer; in such cases perform imaging and image guided core biopsy if a localised suspicious abnormality is present Recurrent central infection is usually associated with periductal mastitis—a smoking related disease—and total duct excision is often needed

Purpose Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability. Methods Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans , 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects. Results In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects. Conclusion Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

Globally, there are an estimated 10.6 million cases of meningitis and 288,000 deaths every year, with the vast majority occurring in low- and middle-income countries. In addition, many survivors suffer from long-term neurological sequelae. Most laboratories assay only for common bacterial etiologies using culture and directed PCR, and the majority of meningitis cases lack microbiological diagnoses, impeding institution of evidence-based treatment and prevention strategies. We report here the results of a validation and application study of using unbiased metagenomic sequencing to determine etiologies of idiopathic (of unknown cause) cases. This included CSF from patients with known neurologic infections, with idiopathic meningitis, and without infection admitted in the largest children’s hospital of Bangladesh and environmental samples. Using mNGS and machine learning, we identified and confirmed an etiology (viral or bacterial) in 40% of idiopathic cases. We detected three instances of Chikungunya virus (CHIKV) that were >99% identical to each other and to a strain previously recognized to cause systemic illness only in 2017. CHIKV qPCR of all remaining stored 472 CSF samples from children who presented with idiopathic meningitis in 2017 at the same hospital uncovered an unrecognized CHIKV meningitis outbreak. CSF mNGS can complement conventional diagnostic methods to identify etiologies of meningitis, and the improved patient- and population-level data can inform better policy decisions. The burden of meningitis in low-and-middle-income countries remains significant, but the infectious causes remain largely unknown, impeding institution of evidence-based treatment and prevention decisions. We conducted a validation and application study of unbiased metagenomic next-generation sequencing (mNGS) to elucidate etiologies of meningitis in Bangladesh. This RNA mNGS study was performed on cerebrospinal fluid (CSF) specimens from patients admitted in the largest pediatric hospital, a World Health Organization sentinel site, with known neurologic infections ( n  = 36), with idiopathic meningitis ( n  = 25), and with no infection ( n  = 30), and six environmental samples, collected between 2012 and 2018. We used the IDseq bioinformatics pipeline and machine learning to identify potentially pathogenic microbes, which we then confirmed orthogonally and followed up through phone/home visits. In samples with known etiology and without infections, there was 83% concordance between mNGS and conventional testing. In idiopathic cases, mNGS identified a potential bacterial or viral etiology in 40%. There were three instances of neuroinvasive Chikungunya virus (CHIKV), whose genomes were >99% identical to each other and to a Bangladeshi strain only previously recognized to cause febrile illness in 2017. CHIKV-specific qPCR of all remaining stored CSF samples from children who presented with idiopathic meningitis in 2017 ( n  = 472) revealed 17 additional CHIKV meningitis cases, exposing an unrecognized meningitis outbreak. Orthogonal molecular confirmation, case-based clinical data, and patient follow-up substantiated the findings. Case-control CSF mNGS surveys can complement conventional diagnostic methods to identify etiologies of meningitis, conduct surveillance, and predict outbreaks. The improved patient- and population-level data can inform evidence-based policy decisions. IMPORTANCE Globally, there are an estimated 10.6 million cases of meningitis and 288,000 deaths every year, with the vast majority occurring in low- and middle-income countries. In addition, many survivors suffer from long-term neurological sequelae. Most laboratories assay only for common bacterial etiologies using culture and directed PCR, and the majority of meningitis cases lack microbiological diagnoses, impeding institution of evidence-based treatment and prevention strategies. We report here the results of a validation and application study of using unbiased metagenomic sequencing to determine etiologies of idiopathic (of unknown cause) cases. This included CSF from patients with known neurologic infections, with idiopathic meningitis, and without infection admitted in the largest children’s hospital of Bangladesh and environmental samples. Using mNGS and machine learning, we identified and confirmed an etiology (viral or bacterial) in 40% of idiopathic cases. We detected three instances of Chikungunya virus (CHIKV) that were >99% identical to each other and to a strain previously recognized to cause systemic illness only in 2017. CHIKV qPCR of all remaining stored 472 CSF samples from children who presented with idiopathic meningitis in 2017 at the same hospital uncovered an unrecognized CHIKV meningitis outbreak. CSF mNGS can complement conventional diagnostic methods to identify etiologies of meningitis, and the improved patient- and population-level data can inform better policy decisions.

Correspondence to Dr BR O'Driscoll, Respiratory Medicine, Level 4 Brooke Building (Orange Area), Salford Royal Foundation NHS Trust, Stott Lane, Salford M6 8HD, UK; ronan.o@driscoll@srft.nhs.uk Contents Abbreviations and symbols used in this guideline Executive summary Summary of recommendations Critical illness requiring high levels of supplemental oxygen Serious illnesses requiring moderate level of supplemental oxygen if the patient is hypoxaemic Conditions for which patients should be monitored closely but oxygen therapy is not required unless the patient is hypoxaemic COPD and other conditions requiring controlled or low-dose oxygen therapy Abbreviations for oxygen devices for use on bedside charts. Chart 1—oxygen prescription guidance for acutely hypoxaemic patients in hospital Chart 2—flow chart for oxygen administration on general wards in hospitals Section 1 Introduction Aim of the guideline Intended users of the guideline and target patient populations Areas covered by the guideline Areas not covered by the guideline Summary of changes since the 2008 guideline Limitations of the guideline Section 2 Methodology of guideline production Establishment of guideline team Summary of key questions How the evidence was assimilated into the guideline Piloting, implementing and auditing the guideline Planned review and updating of the guideline Declarations of interest SIGN levels of evidence SIGN grades of recommendation Section 3 Normal values and definitions Blood gas levels of oxygen and carbon dioxide in health and disease Normal ranges for oxygen saturation (SaO2 and SpO2) and PO2 (PaO2) in the blood at sea level Oxygen saturation in older adults Oxygen saturation at altitude Oxygen saturation in acute and chronic diseases Variation in oxygen saturation during sleep Normal range for arterial carbon dioxide tension Definitions of hypoxaemia, hypoxia, type 1 respiratory failure and hyperoxaemia Definition of hypercapnia and type 2 respiratory failure Definition of acidosis (respiratory acidosis and metabolic acidosis) Mean (SD) PaO2 (kPa and mmHg) and SaO2 (%) values (with range) Ranges, mean, SD, median and IQR values for SpO2 (%) where measurements were made with the patient receiving air for age ≥18 years (n=37 299) from Smith et al Section 4 General blood gas physiology Oxygen physiology Carbon dioxide physiology Concept of target oxygen saturation (SaO2) ranges Section 5 Advanced blood gas physiology and pathophysiology and physiology of oxygen therapy Regulation of blood oxygen content (CaO2) Arterial oxygen tension Haematocrit The oxyhameoglobin dissociation curve and the Bohr effect Regulation of DO2 Pathophysiology of hypoxia and hyperoxia Hypoxaemic hypoxia Other mechanisms of hypoxia Hyperoxia Physiology of carbon dioxide Normal carbon dioxide homoeostasis Regulation of carbon dioxide Pathophysiology of hypercapnia and hypocapnia Mechanisms of hypercapnia and hypocapnia Hypoventilation and hyperventilation Physiology of oxygen therapy Strategies for improving oxygenation and delivery Optimising PaO2 Optimising oxygen carriage Optimising delivery Regulation of CaO2 Ventilatory response to hypoxaemia Oxygen dissociation curve with Bohr effect Total carbon dioxide dissociation curve Effect of PaCO2 Approximate relationship between SaO2 and PaO2 Section 6 Hypoxia, hypoxaemia, hyperoxaemia, hypercapnia and the rationale of targeted oxygen therapy Effects and risks of hypoxia/hypoxaemia and rationale for target oxygen saturation range Desirable oxygen saturation ranges in acute illness Potential benefits of hyperoxaemia and supplemental oxygen therapy in non-hypoxaemic patients Hyperoxaemia has been shown to be beneficial in the following situations Other potential benefits and potential harms of oxygen therapy in non-hypoxaemia patients Potential adverse physiological effects and clinical risks of supplemental oxygen therapy and hyperoxaemia Respiratory system Rebound hypoxaemia following sudden cessation of supplementary oxygen therapy Cardiovascular and cerebrovascular system Reactive oxygen species, tissue toxicity and reports of increased mortality Delay in recognition of physiological deterioration Acute lung injury in patients with acute paraquat poisoning, bleomycin lung injury and acid aspiration Summary of risks of hyperoxaemia and supplemental oxygen therapy Risks of hypercapnia (and respiratory acidosis) Effects of a raised blood carbon dioxide level Clinical signs Risks of acidosis Rationale of oxygen therapy Target oxygen saturation in acute illness Effects of body positioning including restraint systems Physiological effects of acute hypoxaemia and hyperoxaemia Section 7 Clinical and laboratory assessment of hypoxaemia and hypercapnia Assessment of hypoxaemia Clinical assessment of breathless patients and assessment of cyanosis Value and limitation pulse oximetry Arterial and arterialised blood gases Transcutaneous oxygen assessment Assessment of hypercapnia and acidosis Clinical assessment Blood arterial and arteriolar gases Venous PCO2 sampling Carbon dioxide monitors and non-invasive assessments of hypercapnia Section 8 Emergency oxygen use in hospital and healthcare settings Assessment and immediate management of breathless patients on arrival in hospital Differences in management in hospital compared with a prehospital setting Which patients need oxygen therapy? Oxygen saturation target range for most patients Oxygen requirements of specific groups of patients Importance of blood gas measurements in guiding oxygen therapy What should be the initial choice of oxygen delivery system in hospital setting? Devices used in emergency oxygen therapy in hospitals Recommended oxygen therapy for major medical emergencies and critical illness Cardiac arrest and other conditions requiring CPR Critically ill patients including major trauma, shock and major sepsis Drowning Anaphylaxis Major pulmonary haemorrhage or massive haemoptysis Epileptic fits Major head injury Carbon monoxide poisoning Serious illnesses requiring moderate levels of supplemental oxygen if the patient is hypoxaemic Patients with acute onset of hypoxaemia of unknown cause with no pre-existing respiratory disorders or risk factors Acute asthma Pneumonia Lung cancer and other cancers with pulmonary involvement Deterioration of fibrotic lung conditions and other conditions involving parenchymal lung disease or alveolitis Pneumothorax Pleural effusion Pulmonary embolism Acute heart failure Breathlessness due to severe anaemia Sickle cell crisis Recommended oxygen therapy for patients who may be vulnerable to medium or high concentration of oxygen COPD exacerbations Exacerbation of CF Chronic musculoskeletal and neurological disorders Obesity-hypoventilation syndrome Common medical emergencies for which oxygen therapy is indicated only if hypoxaemia is present Acute myocardial infarction, suspected myocardial infarction and acute coronary syndromes Stroke Anxiety and hyperventilation or dysfunctional breathing Poisoning with substances other than carbon monoxide or cyanide Metabolic, endocrine and renal disorders Acute and subacute neuromuscular disorders producing respiratory muscle weakness Cluster headache Obstetric emergencies and labour Use of oxygen in postoperative and perioperative care, including PCA device use Oxygen use, pulse oximetry and the incidence of hypoxaemia in the postoperative period Patient-controlled analgesia The role of hyperoxaemia in reducing postoperative complications Use of oxygen during endoscopy and other procedures involving conscious sedation Use of oxygen in palliative care settings Use of helium–oxygen mixtures (Heliox) Use of CPAP Use of CPAP in perioperative care Use of CPAP in acute pulmonary oedema Section 9 Use of oxygen in ambulances, community and prehospital settings Pulse oximetry and availability of oxygen Clinical assessment by first responder(s) (GP, nurse or ambulance staff) Immediate management of hypoxaemic patients Patients with known COPD Patients who should be assumed to have COPD Other patients at risk of hypercapnic respiratory failure with respiratory acidosis Oxygen alert care and 24% or 28% Venturi masks in patients with COPD (and others at risk of respiratory acidosis) who have had an episode of hypercapnic respiratory failure Choice of devices in prehospital care Emergency use of oxygen in patient's home Use of oxygen by rescue and other non-NHS first responders Use of nitrous oxide/oxygen mixtures (eg, Entonox) Use of oxygen in prehospital care for pregnant women Example of oxygen alert card Section 10 Practical aspects of oxygen therapy Oxygen storage and provision and safety Cylinders Liquid oxygen Oxygen concentrators Patient delivery methods/interfaces High-concentration reservoir mask (non-rebreathing mask) Simple face mask Venturi mask Nasal cannulae High-flow humidified oxygen via nasal cannulae Tracheostomy mask Non-invasive ventilation Oxygen carriage and delivery during patient transport in ambulances Health and Safety Executive guidance for safe use of oxygen cylinders Oxygen use by UK ambulance services Oxygen carriage in other vehicles and in primary care settings and patients' homes Oxygen carriage in private cars (Health and Safety Executive guidance) Medical centres and primary care practices Emergency use of oxygen in the patient's home Oxygen delivery systems in hospitals Perioperative and postoperative care Emergency departments General wards and respiratory departments Devices used in emergency oxygen therapy Flow meters Oxygen tubing and oxygen wall outlets Use of humidified oxygen Rational for use of humidified oxygen Use of bubble humidification systems Large volume nebulisation-based humidifiers Use of oxygen in patients with tracheostomy or laryngectomy Delivering oxygen to patients who require nebulised bronchodilator therapy Nebulised bronchodilator therapy in asthma Nebulised bronchodilator therapy for patients with COPD and other risk facto

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals’ genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current “one-size-fits-all” approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth.

Recurrent apnea with intermittent hypoxia is a major clinical problem in preterm infants. Recent studies, although limited, showed that adults who were born preterm exhibit increased incidence of sleep-disordered breathing and hypertension, suggesting that apnea of prematurity predisposes to autonomic dysfunction in adulthood. Here, we demonstrate that adult rats that were exposed to intermittent hypoxia as neonates exhibit exaggerated responses to hypoxia by the carotid body and adrenal chromaffin cells, which regulate cardio-respiratory function, resulting in irregular breathing with apneas and hypertension. The enhanced hypoxic sensitivity was associated with elevated oxidative stress, decreased expression of genes encoding antioxidant enzymes, and increased expression of pro-oxidant enzymes. Decreased expression of the Sod2 gene, which encodes the antioxidant enzyme superoxide dismutase 2, was associated with DNA hypermethylation of a single CpG dinucleotide close to the transcription start site. Treating neonatal rats with decitabine, an inhibitor of DNA methylation, during intermittent hypoxia exposure prevented oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction. These findings implicate a hitherto uncharacterized role for DNA methylation in mediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype–phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull’s-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes—intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

IntroductionWhile digital technologies can increase the availability and access to evidence-based interventions, little is known about how users engage with them and the mechanisms associated with effective outcomes. Process evaluations are an important component in understanding the aforementioned factors. The ‘SPARX-UK’ study is a randomised controlled pilot and feasibility trial evaluating personalised human-supported (from an ‘eCoach’) vs a self-directed computerised cognitive behavioural therapy intervention (cCBT), called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts), aimed at adolescents with mild to moderate depression. We are comparing supported vs self-directed delivery of SPARX to establish which format should be used in a proposed definitive trial of SPARX. The control is a waitlist group. We will conduct a process evaluation alongside the trial to determine how the intervention is implemented and provide context for interpreting the feasibility trial outcomes. We will also look at the acceptability of SPARX and how users engage with the intervention. This protocol paper describes the rationale, aims and methodology of the SPARX-UK trial process evaluation.Methods and analysisThe process evaluation will use a mixed-methods design following the UK Medical Research Council’s 2015 guidelines, comprising quantitative and qualitative data collection. This will include analysing data usage of participants in the intervention arms; purposively sampled, semi-structured interviews of adolescents, parents/guardians, eCoaches and clinicians/practitioners from the SPARX-UK trial; and analysis of qualitative comments from a survey from those who dropped out early from the trial. Quantitative data will be analysed descriptively. We will use thematic analysis in a framework approach to analyse qualitative data. Quantitative and qualitative data will be mixed and integrated to provide an understanding of how the intervention was implemented and how adolescents interacted with the intervention. This process evaluation will explore the experiences of adolescent participants, parents/guardians, eCoaches and clinicians/practitioners in relation to a complex digital intervention.EthicsEthical approval was granted by the National Health Service (NHS) Health Research Authority South West - Cornwall & Plymouth Research Ethics Committee (Ethics Ref: 22/SW/0149).DisseminationContextualising how the intervention was implemented, and the variations in uptake and engagement, will help us to understand the trial findings in greater depth. The findings from this process evaluation will also inform the decision about whether and how to proceed with a full randomised controlled trial, as well as the development of more effective interventions which can be personalised more precisely via varying levels of human support. We plan to publish the findings of the process evaluation and the wider project in peer-reviewed journals, as well as disseminate via academic conferences.Trial registration numberISRCTN: ISRCTN15124804. Registered on 16 January 2023, https://www.isrctn.com/ISRCTN15124804.

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.