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Health economic evaluations are comparative analyses of alternative courses of action in terms of their costs and consequences. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement, published in 2013, was created to ensure health economic evaluations are identifiable, interpretable, and useful for decision making. It was intended as guidance to help authors report accurately which health interventions were being compared and in what context, how the evaluation was undertaken, what the findings were, and other details that may aid readers and reviewers in interpretation and use of the study. The new CHEERS 2022 statement replaces previous CHEERS reporting guidance. It reflects the need for guidance that can be more easily applied to all types of health economic evaluation, new methods and developments in the field, as well as the increased role of stakeholder involvement including patients and the public. It is also broadly applicable to any form of intervention intended to improve the health of individuals or the population, whether simple or complex, and without regard to context (such as health care, public health, education, social care, etc). This summary article presents the new CHEERS 2022 28-item checklist and recommendations for each item. The CHEERS 2022 statement is primarily intended for researchers reporting economic evaluations for peer reviewed journals as well as the peer reviewers and editors assessing them for publication. However, we anticipate familiarity with reporting requirements will be useful for analysts when planning studies. It may also be useful for health technology assessment bodies seeking guidance on reporting, as there is an increasing emphasis on transparency in decision making. Supplementary Information The online version contains supplementary material available at 10.1186/s12889-021-12491-0.

Objective To assess the impact of reorganisation of neonatal specialist care services in England after a UK Department of Health report in 2003. Design A population-wide observational comparison of outcomes over two epochs, before and after the establishment of managed clinical neonatal networks. Setting Epoch one: 294 maternity and neonatal units in England, Wales, and Northern Ireland, 1 September 1998 to 31 August 2000, as reported by the Confidential Enquiry into Stillbirths and Sudden Deaths in Infancy Project 27/28. Epoch two: 146 neonatal units in England contributing data to the National Neonatal Research Database at the Neonatal Data Analysis Unit, 1 January 2009 to 31 December 2010. Participants Babies born at a gestational age of 27+0-28+6 (weeks+days): 3522 live births in epoch one; 2919 babies admitted to a neonatal unit within 28 days of birth in epoch two. Intervention The national reorganisation of neonatal services into managed clinical networks. Main outcome measures The proportion of babies born at hospitals providing the highest volume of neonatal specialist care (≥2000 neonatal intensive care days annually), having an acute transfer (within the first 24 hours after birth) and/or a late transfer (between 24 hours and 28 days after birth) to another hospital, assessed by change in distribution of transfer category (“none,” “acute,” “late”), and babies from multiple births separated by transfer. For acute transfers in epoch two, the level of specialist neonatal care provided at the destination hospital (British Association of Perinatal Medicine criteria). Results After reorganisation, there were increases in the proportions of babies born at 27-28 weeks’ gestation in hospitals providing the highest volume of neonatal specialist care (18% (631/3495) v 49% (1325/2724); odds ratio 4.30, 95% confidence interval 3.83 to 4.82; P Conclusions There is evidence of some improvement in the delivery of neonatal specialist care after reorganisation. The increase in acute transfers in epoch two, in conjunction with the high proportion transferred to a neonatal unit providing an equivalent or lower level of specialist care, and the continued separation of babies from multiple births, are indicative of poor coordination between maternity and neonatal services to facilitate in utero transfer before delivery, and continuing inadequacies in capacity of intensive care cots. Historical data representing epoch one are available only in aggregate form, preventing examination of temporal trends or confounding factors. This limits the extent to which differences between epochs can be attributed to reorganisation and highlights the importance of routine, prospective data collection for evaluation of future health service reorganisations.

Background Progesterone prophylaxis is widely used to prevent preterm birth but is not licensed and there is little information on long-term outcome. Objective To determine the effect of progesterone prophylaxis in women at high risk of preterm birth on obstetric, neonatal and childhood outcomes. Design Double-blind, randomised placebo-controlled trial. Setting Obstetric units in the UK and Europe between February 2009 and April 2013. Participants Women with a singleton pregnancy who are at high risk of preterm birth because of either a positive fibronectin test or a negative fibronectin test, and either previous spontaneous birth at ≤ 34 weeks+0 of gestation or a cervical length of ≤ 25 mm. Interventions Fibronectin test at 18+0 to 23+0 weeks of pregnancy to determine risk of preterm birth. Eligible women were allocated (using a web-based randomisation portal) to 200 mg of progesterone or placebo, taken vaginally daily from 22+0 to 24+0 until 34+0 weeks’ gestation. Participants, caregivers and those assessing the outcomes were blinded to group assignment until data collection was complete. Main outcome measures There were three primary outcomes, as follows: (1) obstetric – fetal death or delivery before 34+0 weeks’ gestation; (2) neonatal – a composite of death, brain injury on ultrasound scan (according to specific criteria in the protocol) and bronchopulmonary dysplasia; and (3) childhood – the Bayley-III cognitive composite score at 22–26 months of age. Results In total, 96 out of 600 (16%) women in the progesterone group and 108 out of 597 (18%) women in the placebo group had the primary obstetric outcome [odds ratio (OR) 0.86, 95% confidence interval (CI) 0.61 to 1.22]. Forty-six out of 589 (8%) babies of women in the progesterone group and 62 out of 587 (11%) babies of women in the placebo group experienced the primary neonatal outcome [OR 0.72, 95% CI 0.44 to 1.17]. The mean Bayley-III cognitive composite score of the children at 2 years of age was 97.3 points [standard deviation (SD) 17.9 points; n = 430] in the progesterone group and 97.7 points (SD 17.5 points; n = 439) in the placebo group (difference in means –0.48, 95% CI –2.77 to 1.81). Limitations Overall compliance with the intervention was 69%. Harms There were no major harms, although there was a trend of more deaths from trial entry to 2 years in the progesterone group (20/600) than in the placebo group (16/598) (OR 1.26, 95% CI 0.65 to 2.42). Conclusions In this study, progesterone had no significant beneficial or harmful effects on the primary obstetric, neonatal or childhood outcomes.The OPPTIMUM trial is now complete. We intend to participate in a comprehensive individual patient-level data meta-analysis examining women with a singleton pregnancy with a variety of risk factors for preterm birth. Trial registration Current Controlled Trials ISRCTN14568373. Funding This trial was funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership.

The relationship between health care expenditure and health outcomes has been the subject of recent academic inquiry in order to inform cost-effectiveness thresholds for health technology assessment agencies. Previous studies in public health systems have relied upon data aggregated at the national or regional level; however, there remains debate about whether the supply side effect of changes to expenditure are identifiable using data at this level of aggregation. We use detailed patient data derived from electronic neonatal records across England along with routinely available cost data to estimate the effect of changes to patient expenditure on clinical health outcomes in a well-defined patient population. A panel of 32 neonatal intensive care units for the period 2009-2013 was constructed. Accounting for the potential endogeneity of expenditure a 100 pound increase in the cost per intensive care cot day (sample average cost: 1,127) pound is estimated to reduce the risk of mortality of 0.38 percentage points (sample average mortality: 11.0%) in neonatal intensive care. This translates into a cost per life saved in neonatal intensive care of approximately 420,000 pound.

Background Process evaluation is increasingly common alongside complex randomised controlled trials (RCTs). This evaluation helps in understanding the mechanisms of impact and how the study processes were executed, and it includes any contextual factors which may have implications for the trial results and any future implementation. This process evaluation is for the Chronic Headache Education and Self-management Study (CHESS) RCT, which is evaluating an education and self-management group behavioural intervention for people with chronic headache. Chronic headache is defined as headaches which are present for 15 or more days per month. The most common types are chronic migraine and chronic tension type and medication overuse headaches. Methods We will use a mixed methods approach. Quantitative data will be taken from routine trial data which will help us to assess the reach of the study; i.e. did we reach those whom we expected and from where? Intervention attendance (dose received) and attrition and qualitative data will augment our understanding about reasons why people may not wish to take part in or failed to attend sessions. Interviews with intervention facilitators and trial participants will gain different perspectives on taking part in the trial. Fidelity will be assessed through listening to audio recordings for adherence to course content and competence of the facilitation of a sample of sessions. Discussion Our process evaluation will allow us to gain insight into how the trial was delivered, the obstacles and enablers encountered and the possible reasons why the interventions may or may not be effective. Trial registration ISRCTN79708100. Registered on 16 December 2015. Electronic supplementary material The online version of this article (10.1186/s13063-019-3372-x) contains supplementary material, which is available to authorized users.

A new methodological framework for assessing agreement between cost-effectiveness endpoints generated using alternative sources of data on treatment costs and effects for trial-based economic evaluations is proposed. The framework can be used to validate cost-effectiveness endpoints generated from routine data sources when comparable data is available directly from trial case report forms or from another source. We illustrate application of the framework using data from a recent trial-based economic evaluation of the probiotic Bifidobacterium breve strain BBG administered to babies less than 31 weeks of gestation. Cost-effectiveness endpoints are compared using two sources of information; trial case report forms and data extracted from the National Neonatal Research Database (NNRD), a clinical database created through collaborative efforts of UK neonatal services. Focusing on mean incremental net benefits at £30,000 per episode of sepsis averted, the study revealed no evidence of discrepancy between the data sources (two-sided p values >0.4), low probability estimates of miscoverage (ranging from 0.039 to 0.060) and concordance correlation coefficients greater than 0.86. We conclude that the NNRD could potentially serve as a reliable source of data for future trial-based economic evaluations of neonatal interventions. We also discuss the potential implications of increasing opportunity to utilize routinely available data for the conduct of trial-based economic evaluations.

Objective Given the continuing debate about the benefits of caesarean section for very preterm infants, we sought to describe caesarean section rates for infants between 28 and 31 weeks of gestation in European regions and their association with regional mortality and short-term morbidity. Study design Singletons and twins without lethal congenital anomalies alive at onset of labour from 28 to 31 weeks of gestation from the 2003 MOSAIC cohort of very preterm births in 10 European regions were analysed (N = 3310). Determinants included maternal and fetal characteristics as well as regional caesarean section rates for all births. We explored correlations between caesarean section rates and mortality and morbidity on the regional level. Results 95% of infants from pregnancies complicated by hypertension or severe growth restriction detected antenatally were delivered by caesarean section (regional range: 90–100%) versus 55.4% (range: 29–84%) for other pregnancies. Regional caesarean section rates for births at all gestations ranged from 14% to 38% and were correlated with very preterm caesarean rates (p = 0.011). Determinants of caesarean section differed between regions with high versus low rates: multiples were more likely to be born by caesarean section in regions with high rates. There were no regional level correlations between caesarean section rates and mortality and morbidity. Conclusions With the exception of pregnancies with hypertension and growth restriction, there was broad variation in very preterm caesarean section rates between regions after adjustment for clinical factors. Given maternal risks associated with caesarean section, more research on its optimal use for very preterm deliveries is necessary.

Summary Background Systemic sepsis is a major cause of death in preterm neonates. There are compelling theoretical reasons why treatment with haemopoietic colony-stimulating factors might reduce sepsis and improve outcomes, and as a consequence these agents have entered into use in neonatal medicine without adequate evidence. We assessed whether granulocyte-macrophage colony stimulating factor (GM-CSF) administered as prophylaxis to preterm neonates at high risk of neutropenia would reduce sepsis, mortality, and morbidity. Methods We undertook a single-blind, multicentre, randomised controlled trial in 26 centres between June, 2000, and June, 2006. 280 neonates of below or equal to 31 weeks' gestation and below the 10th centile for birthweight were randomised within 72 h of birth to receive GM-CSF 10 μg/kg per day subcutaneously for 5 days or standard management. From recruitment to day 28 a detailed daily clinical record form was completed by the treating clinicians. Primary outcome was sepsis-free survival to 14 days from trial entry. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN42553489. Findings Neutrophil counts after trial entry rose significantly more rapidly in infants treated with GM-CSF than in control infants during the first 11 days (difference between neutrophil count slopes 0·34×10 9 /L/day; 95% CI 0·12–0·56). There was no significant difference in sepsis-free survival for all infants (93 of 139 treated infants, 105 of 141 control infants; difference −8%, 95% CI −18 to 3). A meta-analysis of this trial and previous published prophylactic trials showed no survival benefit. Interpretation Early postnatal prophylactic GM-CSF corrects neutropenia but does not reduce sepsis or improve survival and short-term outcomes in extremely preterm neonates. Funding Action Medical Research.

Introduction Femoroacetabular impingement (FAI) syndrome is a recognised cause of young adult hip pain. There has been a large increase in the number of patients undergoing arthroscopic surgery for FAI; however, a recent Cochrane review highlighted that there are no randomised controlled trials (RCTs) evaluating treatment effectiveness. We aim to compare the clinical and cost-effectiveness of arthroscopic surgery versus best conservative care for patients with FAI syndrome.\ud \ud Methods We will conduct a multicentre, pragmatic, assessor-blinded, two parallel arm, RCT comparing arthroscopic surgery to physiotherapy-led best conservative care. 24 hospitals treating NHS patients will recruit 344 patients over a 26-month recruitment period. Symptomatic adults with radiographic signs of FAI morphology who are considered suitable for arthroscopic surgery by their surgeon will be eligible. Patients will be excluded if they have radiographic evidence of osteoarthritis, previous significant hip pathology or previous shape changing surgery. Participants will be allocated in a ratio of 1:1 to receive arthroscopic surgery or conservative care. Recruitment will be monitored and supported by qualitative intervention to optimise informed consent and recruitment. The primary outcome will be pain and function assessed by the international hip outcome tool 33 (iHOT-33) measured 1-year following randomisation. Secondary outcomes include general health (short form 12), quality of life (EQ5D-5L) and patient satisfaction. The primary analysis will compare change in pain and function (iHOT-33) at 12 months between the treatment groups, on an intention-to-treat basis, presented as the mean difference between the trial groups with 95% CIs. The study is funded by the Health Technology Assessment Programme (13/103/02).\ud \ud Ethics and dissemination Ethical approval is granted by the Edgbaston Research Ethics committee (14/WM/0124). The results will be disseminated through open access peer-reviewed publications, including Health Technology Assessment, and presented at relevant conferences.\ud \ud Trial registration number ISRCTN64081839; Pre-results.

Although high income countries have made substantial progress towards reducing child mortality over recent decades, rates vary markedly between and within countries, and modifiable factors continue to be identified in many deaths. A series of three articles in The Lancet has described the epidemiology of child mortality and a standardised approach to child death reviews in high income countries. Patterns of child mortality at different ages are delineated into five broad categories: perinatal, congenital, acquired natural, external, and unexplained; while contributory factors are described across four broad domains: factors intrinsic to the child, the physical environment, the social environment, and service delivery. This commentary attempts to draw on the conclusions of these three articles and make practical recommendations on strategies in three key areas with perhaps the greatest potential to further reduce child mortality in high income countries: perinatal conditions, particularly preterm birth; acquired natural conditions, such as sepsis or acute respiratory problems; and external causes, including road traffic fatalities.

Musculoskeletal shoulder problems are common after breast cancer treatment. Early postoperative exercises targeting the upper limb may improve shoulder function. This protocol describes a National Institute for Health Research-funded randomised controlled trial (RCT) to evaluate the clinical and cost-effectiveness of an early supervised structured exercise programme compared with usual care, for women at high risk of developing shoulder problems after breast cancer surgery.MethodsThis pragmatic two-armed, multicentre RCT is underway within secondary care in the UK. PRevention Of Shoulder ProblEms tRial (PROSPER) aims to recruit 350 women from approximately 15 UK centres with follow-up at 6 weeks, 6 and 12 months after randomisation. Recruitment processes and intervention development were optimised through qualitative research during a 6-month internal pilot phase. Participants are randomised to the PROSPER intervention or best practice usual care only. The PROSPER intervention is delivered by physiotherapists and incorporates three main components: shoulder-specific exercises targeting range of movement and strength; general physical activity and behavioural strategies to encourage adherence and support exercise behaviour. The primary outcome is upper arm function assessed using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire at 12 months postrandomisation. Secondary outcomes include DASH subscales, acute and chronic pain, complications, health-related quality of life and healthcare resource use. We will interview a subsample of 20 participants to explore their experiences of the trial interventions.DiscussionThe PROSPER study is the first multicentre UK clinical trial to investigate the clinical and cost-effectiveness of supported exercise in the prevention of shoulder problems in high-risk women undergoing breast cancer surgery. The findings will inform future clinical practice and provide valuable insight into the role of physiotherapy-supported exercise in breast cancer rehabilitation.Protocol versionVersion 2.1; dated 11 January 2017Trial registration numberISRCTN35358984; Pre-results.

Contains fulltext : 88875.pdf (Publisher’s version ) (Closed access) BACKGROUND: About 10% of twins are born before 32 weeks of gestation and very preterm birth rates are increasing. Preterm twins tend to have more favourable outcomes than singletons of the same gestational age, but fewer data are available for very preterm infants. This study aims to determine whether outcomes differ between very preterm twins and singletons. METHOD: This study was of a population-based cohort of very preterm babies in 10 European regions in 2003. Mortality and morbidity to discharge from hospital were compared for twins and singletons between 24 and 31 weeks of gestation, who were alive at the onset of labour and without lethal congenital anomalies. Clinical characteristics, pregnancy complications and healthcare factors were taken into consideration. RESULTS: Between 28 and 31 weeks of gestation, mortality and oxygen dependency at 36 corrected weeks of gestation were lower for twins than singletons (3.9 versus 6.5% and 7.1 versus 10.4%, respectively), but this advantage disappeared after controlling for medical and healthcare factors. Hypertension, growth restriction and haemorrhaging were less frequent complications of twin birth and more twins received antenatal corticosteroids and were born in level III units. In contrast, between 24 and 27 weeks of gestation, twins had higher adjusted risks of mortality and Grade III/IV intraventricular haemorrhaging [adjusted ORs 1.5 (95% CI 1.1-2.2) and 1.5 (1.0-2.1)]. These adverse outcomes were concentrated among twins from same sex pairs with discordant birthweights. CONCLUSIONS: Between 24 and 27 weeks of gestation, risks of mortality and severe cranial haemorrhaging were higher for twins than singletons if they were from same sex pairs with discordant birthweights. 01 april 2010

OBJECTIVES. We sought to compare guidelines for level III units in 10 European regions and analyze the characteristics of neonatal units that care for very preterm infants. METHODS. The MOSAIC (Models of Organising Access to Intensive Care for Very Preterm Births) project combined a prospective cohort study on all births between 22 and 31 completed weeks of gestation in 10 European regions and a survey of neonatal unit characteristics. Units that admitted ≥5 infants at RESULTS. Six of 9 guidelines for level III units included minimum size criteria, based on number of intensive care beds (6 guidelines), neonatal admissions (2), ventilated patients (1), obstetric intensive care beds (1), and deliveries (2). The characteristics of level III units varied, and many were small or unspecialized by recommended criteria: 36% had fewer than 50 very preterm annual admissions, 22% ventilated fewer than 50 infants annually, and 28% had fewer than 6 intensive care beds. Level II units were less specialized, but some provided mechanical ventilation (57%) or high-frequency ventilation (20%) or had neonatal surgery facilities (17%). Sixty-nine percent of level III and 36% of level I or II units had continuous medical coverage by a qualified pediatrician. Twenty-two percent of infants who were CONCLUSIONS. No consensus exists in Europe about size or other criteria for NICUs. A better understanding of the characteristics associated with high-quality neonatal care is needed, given the high proportion of very preterm infants who are cared for in units that are considered small or less specialized by many recommendations.

Objectives To characterize early childhood social-communication skills and autistic traits in children born very preterm using the Quantitative Checklist for Autism in Toddlers (Q-CHAT) and explore neonatal and sociodemographic factors associated with Q-CHAT scores. Study design Parents of children born before 30 weeks gestation and enrolled in a study evaluating routinely collected neurodevelopmental data between the post-menstrual ages of 20 and 28 months were invited to complete the Q-CHAT questionnaire. Children with severe neurosensory disabilities and cerebral palsy were excluded. Participants received neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III). Q-CHAT scores of this preterm cohort were compared with published general population scores. The association between Bayley-III cognitive and language scores and neonatal and sociodemographic factors with Q-CHAT scores were examined. Results Q-CHAT questionnaires were completed from 141 participants. At a mean post-menstrual age of 24 months, the Q-CHAT scores of the preterm cohort (mean 33.7, SD 8.3) were significantly higher than published general population scores (mean 26.7; SD 7.8), indicating greater social-communication difficulty and autistic behavior. Preterm children received higher scores, particularly in the categories of restricted, repetitive, stereotyped behavior, communication, and sensory abnormalities. Lower Bayley-III language scores and non-white ethnicity were associated with higher Q-CHAT scores. Conclusions Preterm children display greater social-communication difficulty and autistic behavior than the general population in early childhood as assessed by the Q-CHAT. The implications for longer-term outcome will be important to assess.

Background Linkage between routinely collected hospital birth and other records offers the potential for epidemiological and public health research by developing population-level birth cohorts with cradle-to-grave follow-up. Data from births in English National Health Service hospitals are collected in the Hospital Episode Statistics (HES) database but are of uncertain quality. Methods We examined the range and completeness of birth information recorded in HES and tested an approach for minimizing the effect of hospital-level variations by selecting hospitals with high completeness of recording (≥90%) for key fields. We discuss important methodological considerations when using routine healthcare data to develop a birth cohort. Results The proportion of missing data in key birth record fields has been decreasing annually, such as gestational age and birth weight (from 46.2 and 43.9% in 2005/06 to 18.1 and 16.9% in 2009/10, respectively). We compared the important characteristics such as size and access to specialist neonatal care between 71 high-coding and 85 low-coding hospitals and found no significant differences, suggesting hospitals with high birth record completeness may be generalizable and representative of all hospitals. Conclusions The completeness of recording of hospital birth information varies greatly between hospitals in England but is improving. It may be preferable and valid to construct cohorts from only hospitals with high completeness of recording.

Objective To assess the impact of being small for gestational age (SGA) on very preterm mortality and morbidity rates by using different birthweight percentile thresholds and whether these effects differ by the cause of the preterm birth. Study design The study included singletons and twins alive at onset of labor between 24 and 31 weeks of gestation without congenital anomalies from the Models of Organising Access to Intensive Care for very preterm births very preterm cohort in 10 European regions in 2003 (n = 4525). Outcomes were mortality, intraventricular hemorrhage grade III and IV, cystic periventricular leukomalacia, and bronchopulmonary dysplasia (BPD). Birthweight percentiles in 6 classes were analyzed by pregnancy complication. Results The mortality rate was higher for infants with birthweights Conclusions A 25th percentile cutoff point was a means of identifying infants at higher risk of death and a continuous measure better described risks of BPD. Lower birthweights were associated with poor outcomes regardless of pregnancy complications.

Contains fulltext : 88841.pdf (Publisher’s version ) (Closed access) Survival and quality of life are improved for very preterm babies when delivery occurs in a maternity unit with on-site neonatal intensive care (level III unit). We investigated the impact of distance on the probability of delivering in such a unit for births before 32 weeks of gestation from 9 European regions with diverse perinatal health systems (the MOSAIC cohort). We analysed distances between women's homes, and the nearest level III in population quartiles, adjusting for maternal and pregnancy characteristics. Living farther away from a level III reduced access to specialised care everywhere; in some regions women residing in the fourth quartile were half as likely to deliver in level III units as those in the first. To improve regionalized perinatal care the spatial location of level III units should be taken into account. 01 mei 2010

Carbapenem antibiotics were first introduced in the 1980s and have long been considered the most active agents for the treatment of multidrug-resistant gram-negative bacteria. Over the last decade, carbapenem-resistant Enterobacteriaceae (CRE) have emerged as organisms causing spontaneous bacterial peritonitis. Infections caused by CRE have shown a higher mortality rate than those caused by bacteria sensitive to carbapenem antibiotics. Current antibiotic guidelines for the treatment of spontaneous bacterial peritonitis are insufficient, and rapid de-escalation of empiric antibiotic treatment is not widely recognized. This review summarizes the molecular characteristics, epidemiology and possible treatment of spontaneous bacterial peritonitis caused by CRE.

Background: Systemic lupus erythematosus (SLE) is a chronic, auto-immune, multi-organ disease that can affect both the skin and the lungs. Malar rash is a common skin manifestation of SLE and is linked to SLE disease activity, whereas lung involvement is a generally negative prognostic factor for these patients. However, a sensitive and non-invasive screening tool for potential lung involvement in SLE patients is still not available. Methods: This study aimed to investigate the relationship between malar rash and airway inflammation in adult SLE patients who were not known to have any lung involvement (clinical or radiologic). The study comprised of the measurement of the concentration of NO in exhaled breath or fraction of exhaled nitric oxide (FeNO) and levels were compared between those with and without malar rash. This tool is considered as a sensitive and non-invasive method that is routinely used in patients with asthma or other respiratory diseases to identify airway inflammation. Results: A total of 125 patients (100 females, 25 males) were enrolled during the study period from January 2011 to December 2014. Patients with malar rash (N = 35) had a significant decrease in serum levels of C4 (p < 0.05) compared to patients without malar rash (N = 90). The mean levels of FeNO in overall patients were 36.44 ± 8.87 ppb. A statistically significant difference in FeNO50 values between patients with malar rash (43.46 ± 6.72 ppb) and without (29.43 ± 3.64 ppb) was found (p < 0.001). FeNO50 values were inversely correlated only with serum C4 (p < 0.01). However, no correlation between FeNO50 values and SLE clinical disease activity scores was found. Conclusions: The presence of a malar rash may predict sub-clinical airway inflammation in SLE patients. Further prospective studies are needed to confirm the usefulness of FeNO measurements in monitoring SLE-associated airway inflammation.

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

AIM To evaluate the outcomes in biological treatment and quality of life of psoriatic patients with chronic hepatitis C (CHC) treated with new Direct-Acting Antiviral agents (DAAs) compared to pegylated interferon-2α plus ribavirin (P/R) therapy. METHODS This is a retrospective study involving psoriatic patients in biological therapy who underwent anti-hepatitis C virus (HCV) treatment at the Department of Dermatology Galeazzi Orthopaedic Institute Milan, Italy from January 2010 to November 2017. The patients were divided into two groups: patients that underwent therapy with DAAs and patients that underwent HCV treatment with P/R. Patients were assessed by a dermatologist for psoriasis symptoms, collecting Psoriasis Area Severity Index (PASI) scores and the Dermatology Quality of Life Index (DLQI). PASI and DLQI scores were evaluated 24 wk after the end of HCV treatment and were assumed as an outcome of the progression of psoriasis. Switching to a different bDMARD was considered as an inadequate response to biological therapy. The dropout of HCV therapy and sustained virological response (SVR) were considered as outcomes of HCV therapy. RESULTS Fifty-nine psoriatic patients in biological therapy underwent antiviral therapy for CHC. Of this, 27 patients were treated with DAAs and 32 with P/R. After 24 wk post treatment, the DLQI and the PASI scores were significantly lower (P < 0.001 and P < 0.005, respectively) in the DAAs group compared with P/R group. None of the patients in the DAAs group (0/27) compared to 8 patients of the P/R group (8/32) needed a shift in biological treatment. CONCLUSION DAAs seem to be more effective and safe than P/R in HCV-positive psoriatic patients on biological treatment. Fewer dermatological adverse events may be due to interferon-free therapy.

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Objective To compare the effectiveness and acceptability of outpatient polypectomy with inpatient polypectomy. Design Pragmatic multicentre randomised controlled non-inferiority study. Setting Outpatient hysteroscopy clinics in 31 UK National Health Service hospitals. Participants 507 women who attended as outpatients for diagnostic hysteroscopy because of abnormal uterine bleeding and were found to have uterine polyps. Interventions Participants were randomly assigned to either outpatient uterine polypectomy under local anaesthetic or inpatient uterine polypectomy under general anaesthesia. Data were collected on women’s self reported bleeding symptoms at baseline and at 6, 12, and 24 months. Data were also collected on pain and acceptability of the procedure at the time of polypectomy. Main outcome measures The primary outcome was successful treatment, determined by the women’s assessment of bleeding at six months, with a prespecified non-inferiority margin of 25%. Secondary outcomes included generic (EQ-5D) and disease specific (menorrhagia multi-attribute scale) quality of life, and feasibility and acceptability of the procedure. Results 73% (166/228) of women in the outpatient group and 80% (168/211) in the inpatient group reported successful treatment at six months (intention to treat relative risk 0.91, 95% confidence interval 0.82 to 1.02; per protocol relative risk 0.92, 0.82 to 1.02). Failure to remove polyps was higher (19% v 7%; relative risk 2.5, 1.5 to 4.1) and acceptability of the procedure was lower (83% v 92%; 0.90, 0.84 to 0.97) in the outpatient group Quality of life did not differ significantly between the groups. Four uterine perforations, one of which necessitated bowel resection, all occurred in the inpatient group. Conclusions Outpatient polypectomy was non-inferior to inpatient polypectomy. Failure to remove a uterine polyp was, however, more likely with outpatient polypectomy and acceptability of the procedure was slightly lower. Trial registration International Clinical Trials Registry 65868569.

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31 %). Remarkably, a recurrent de novo mutation, c. 959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity. Refereed/Peer-reviewed

OBJECTIVE: Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. METHODS: Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. RESULTS: Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. INTERPRETATION: PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease.

We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies. Refereed/Peer-reviewed

Rare GABAA receptor γ2 and α1 subunit mutations of pathogenic effect have been described segregating in families with “monogenic” epilepsies. We now report globally on the genetic variation contained within all 16 neuronal GABAA receptor subunit genes from the one patient cohort. The cohort consists of GEFS+, FS, and IGE subgroups as either sporadic cases or index cases from small families, with one index case from one large IGE family. The rarity of mutations and coding variation in general across all of the subunits suggests a low tolerance for mutations affecting GABA mediated neuronal inhibition. Characterization of the broader channelopathy load associated with susceptibility to these common epilepsies mostly with complex genetics will need to be expanded beyond the family of GABAA receptor subunits to all families of neuronal ion channels and their interacting molecules by systematic mutation detection associated with functional investigation of their naturally occurring genetic variations. Refereed/Peer-reviewed