No exponential rise in revision knee replacement surgery over the past 15 years: an analysis from the National Joint Registry.

OBJECTIVE: To investigate trends in the incidence rate and the main indication for revision knee replacement (rKR) over the past 15 years in the UK. METHOD: Repeated national cross-sectional study from 2006 to 2020 using data from the National Joint Registry (NJR). Crude incidence rates were calculated using population statistics from the Office for National Statistics. RESULTS: Annual total counts of rKR increased from 2,743 procedures in 2006 to 6,819 procedures in 2019 (149% increase). The incidence rate of rKR increased from 6.3 per 100,000 adults in 2006 (95% CI 6.1 to 6.5) to 14 per 100,000 adults in 2019 (95% CI 14 to 14) (122% increase). Annual increases in the incidence rate of rKR became smaller over the study period. There was a 43.6% reduction in total rKR procedures in 2020 (during the Covid-19 pandemic) compared to 2019. Aseptic loosening was the most frequent indication for rKR overall (20.7% procedures). rKR for aseptic loosening peaked in 2012 and subsequently decreased. rKR for infection increased incrementally over the study period to become the most frequent indication in 2019 (2.7 per 100,000 adults [95% CI 2.6 to 2.9]). Infection accounted for 17.1% first linked rKR, 36.5% second linked rKR and 49.4% third or more linked rKR from 2014 to 2019. CONCLUSIONS: Recent trends suggest slowing of the rate of increase in the incidence of rKR. Infection is now the most common indication for rKR, following recent decreases in rKR for aseptic loosening. Infection was prevalent in re-revision KR procedures.

Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement: updated reporting guidance for health economic evaluations.

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.

Protocol for the Weight-bearing in Ankle Fractures (WAX) trial: a multicentre prospective non-inferiority trial of early versus delayed weight-bearing after operatively managed ankle fracture.

BACKGROUND: Unstable ankle fractures represent a substantial burden of disease, accounting for a mean hospital stay of nine days, a mean cost of £4,491 per patient and 20,000 operations per year. There is variation in UK practice around weight-bearing instructions after operatively managed ankle fracture. Early weight-bearing may reduce reliance on health services, time off work, and improve functional outcomes. However, concerns remain about the potential for complications such as implant failure. This is the protocol of a multicentre randomised non-inferiority clinical trial of weight-bearing following operatively treated ankle fracture. METHODS: Adults aged 18 years and over who have been managed operatively for ankle fracture will be assessed for eligibility. Baseline function (Olerud and Molander Ankle Score [OMAS]), health-related quality of life (EQ-5D-5L), and complications will be collected after informed consent has been obtained. A randomisation sequence has been prepared by a trial statistician to allow for 1:1 allocation to receive either instruction to weight-bear as pain allows from the point of randomisation, two weeks after the time of surgery ('early weight-bearing' group) or to not weight-bear for a further four weeks ('delayed weight -bearing' group). All other treatment will be as per the guidance of the treating clinician. Participants will be asked about their weight-bearing status weekly until four weeks post-randomisation. At four weeks post-randomisation complications will be collected. At six weeks, four months, and 12 months post-randomisation, the OMAS, EQ-5D-5L, complications, physiotherapy input, and resource use will be collected. The primary outcome measure is ankle function (OMAS) at four months post-randomisation. A minimum of 436 participants will be recruited to obtain 80% power to detect a non-inferiority margin of -6 points on the OMAS 4 months post-randomisation. A within-trial health economic evaluation will be conducted to estimate the cost-effectiveness of the treatment options. DISCUSSION: The results of this study will inform national guidance with regards to the most clinically and cost-effective strategy for weight-bearing after surgery for unstable ankle fractures. TRIAL REGISTRATION: ISRCTN12883981 , Registered 02 December 2019.

Peripartum hysterectomy: an economic analysis of direct healthcare costs using routinely collected data.

OBJECTIVE: To estimate resource use and costs associated with peripartum hysterectomy for the English National Health Service. DESIGN/SETTING: Analysis of linked Clinical Practice Research Datalink and Hospital Episodes Statistics (CPRD-HES) data. POPULATION: Women undergoing peripartum hysterectomy between 1997 and 2013 and matched controls. METHODS: Inverse probability weighted generalised estimating equations were used to model the non-linear trend in healthcare service use and costs over time, accounting for missing data, adjusting for maternal age, body mass index, delivery year, smoking and socio-economic indicators. MAIN OUTCOME MEASURES: Primary care, hospital outpatient and inpatient attendances and costs (UK 2015 prices). RESULTS: The study sample included 1362 women (192 cases and 1170 controls) who gave birth between 1997 and 2013; 1088 (153 cases and 935 controls) of these were deliveries between 2003 and 2013 when all categories of hospital resource use were available. Based on the 2003-2013 delivery cohort, peripartum hysterectomy was associated with a mean adjusted additional total cost of £5380 (95% CI £4436-6687) and a cost ratio of 1.76 (95% CI 1.61-1.98) over 5 years of follow up compared with controls. Inpatient costs, mostly incurred during the first year following surgery, accounted for 78% excluding or 92% including delivery-related costs. CONCLUSION: Peripartum hysterectomy is associated with increased healthcare costs driven largely by increased post-surgery hospitalisation rates. To reduce healthcare costs and improve outcomes for women who undergo hysterectomy, interventions that reduce avoidable repeat hospitalisations following surgery such as providing active follow up, treatment and support in the community should be considered. TWEETABLE ABSTRACT: A large amount of NHS data on peripartum hysterectomy suggests active community follow up could reduce costs, #HealthEconomics.

Economic costs associated with moderate and late preterm birth: a prospective population-based study.

OBJECTIVE: We sought to determine the economic costs associated with moderate and late preterm birth. DESIGN: An economic study was nested within a prospective cohort study. SAMPLE: Infants born between 32(+0) and 36(+6)  weeks of gestation in the East Midlands of England. A sample of infants born at ≥37 weeks of gestation acted as controls. METHODS: Data on resource use, estimated from a National Health Service (NHS) and personal social services perspective, and separately from a societal perspective, were collected between birth and 24 months corrected age (or death), and valued in pounds sterling, at 2010-11 prices. Descriptive statistics and multivariable analyses were used to estimate the relationship between gestational age at birth and economic costs. MAIN OUTCOME MEASURES: Cumulative resource use and economic costs over the first two years of life. RESULTS: Of all eligible births, 1146 (83%) preterm and 1258 (79%) term infants were recruited. Mean (standard error) total societal costs from birth to 24 months were £12 037 (£1114) and £5823 (£1232) for children born moderately preterm (32(+0) -33(+6)  weeks of gestation) and late preterm (34(+0) -36(+6)  weeks of gestation), respectively, compared with £2056 (£132) for children born at term. The mean societal cost difference between moderate and late preterm and term infants was £4657 (bootstrap 95% confidence interval, 95% CI £2513-6803; P < 0.001). Multivariable regressions revealed that, after controlling for clinical and sociodemographic characteristics, moderate and late preterm birth increased societal costs by £7583 (£874) and £1963 (£337), respectively, compared with birth at full term. CONCLUSIONS: Moderate and late preterm birth is associated with significantly increased economic costs over the first 2 years of life. Our economic estimates can be used to inform budgetary and service planning by clinical decision-makers, and economic evaluations of interventions aimed at preventing moderate and late preterm birth or alleviating its adverse consequences. TWEETABLE ABSTRACT: Moderate and late preterm birth is associated with increased economic costs over the first 2 years of life.

Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy.

In excitatory neurons, SCN2A (NaV1.2) and SCN8A (NaV1.6) sodium channels are enriched at the axon initial segment. NaV1.6 is implicated in several mouse models of absence epilepsy, including a missense mutation identified in a chemical mutagenesis screen (Scn8a(V929F)). Here, we confirmed the prior suggestion that Scn8a(V929F) exhibits a striking genetic background-dependent difference in phenotypic severity, observing that spike-wave discharge (SWD) incidence and severity are significantly diminished when Scn8a(V929F) is fully placed onto the C57BL/6J strain compared with C3H. Examination of sequence differences in NaV subunits between these two inbred strains suggested NaV1.2(V752F) as a potential source of this modifier effect. Recognising that the spatial co-localisation of the NaV channels at the axon initial segment (AIS) provides a plausible mechanism for functional interaction, we tested this idea by undertaking biophysical characterisation of the variant NaV channels and by computer modelling. NaV1.2(V752F) functional analysis revealed an overall gain-of-function and for NaV1.6(V929F) revealed an overall loss-of-function. A biophysically realistic computer model was used to test the idea that interaction between these variant channels at the AIS contributes to the strain background effect. Surprisingly this modelling showed that neuronal excitability is dominated by the properties of NaV1.2(V752F) due to "functional silencing" of NaV1.6(V929F) suggesting that these variants do not directly interact. Consequent genetic mapping of the major strain modifier to Chr 7, and not Chr 2 where Scn2a maps, supported this biophysical prediction. While a NaV1.6(V929F) loss of function clearly underlies absence seizures in this mouse model, the strain background effect is apparently not due to an otherwise tempting Scn2a variant, highlighting the value of combining physiology and genetics to inform and direct each other when interrogating genetic complex traits such as absence epilepsy.

Standardizing a method for functional assessment of neural networks in brain organoids.

During the last decade brain organoids have emerged as an attractive model system, allowing stem cells to be differentiated into complex 3D models, recapitulating many aspects of human brain development. Whilst many studies have analysed anatomical and cytoarchitectural characteristics of organoids, their functional characterisation has been limited, and highly variable between studies. Standardised, consistent methods for recording functional activity are critical to providing a functional understanding of neuronal networks at the synaptic and network level that can yield useful information about functional network phenotypes in disease and healthy states. In this study we outline a detailed methodology for calcium imaging and Multi-Electrode Array (MEA) recordings in brain organoids. To illustrate the utility of these functional interrogation techniques in uncovering induced differences in neural network activity we applied various stimulating media protocols. We demonstrate overlapping information from the two modalities, with comparable numbers of active cells in the four treatment groups and an increase in synchronous behaviour in BrainPhys treated groups. Further development of analysis pipelines to reveal network level changes in brain organoids will enrich our understanding of network formation and perturbation in these structures, and aid in the future development of drugs that target neurological disorders at the network level.

Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.

Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance.The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication. The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website (www.ispor.org/TaskForces/EconomicPubGuidelines.asp). We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in 5 years.

Standard- or high-dose oxytocin for nulliparous women with confirmed delay in labour: quantitative and qualitative results from a pilot randomised controlled trial.

OBJECTIVE: Evidence suggests that a high dose of oxytocin for nulliparous women at 37-42 weeks of gestation with confirmed delay in labour increases spontaneous vaginal birth. We undertook a pilot study to test the feasibility of this treatment. DESIGN: Pilot double-blind randomised controlled trial. SETTING: Three teaching hospitals in the UK. POPULATION: A total of 94 consenting nulliparous women at term with confirmed delay in labour were recruited, and 18 were interviewed. METHODS: Women were assigned to either a standard (2 mU/min, increasing every 30 minutes to 32 mU/minute) or a high-dose regimen (4 mU/minute, increasing every 30 minutes to 64 mU/minutes) oxytocin by computer-generated randomisation. Simple descriptive statistics were used, as the sample size was insufficient to evaluate clinical outcomes. The constant comparative method was used to analyse the interviews. MAIN OUTCOMES MEASURES: The main outcome measures: number of women eligible; maternal and neonatal birth; safety; maternal psychological outcomes and experiences; health-related quality of life outcomes using validated tools and data on health service resource use; incidence of suspected delay of labour (cervical dilatation of <2 cm after 4 hours, once labour is established); and incidence of confirmed delay of labour (progress of <1 cm on repeat vaginal examination after a period of 2 hours). RESULTS: We successfully developed systems to recruit eligible women in labour and to collect data. Rates of spontaneous vaginal birth (10/47 versus 12/47, RR 1.2, 95% CI 0.6-2.5) and caesarean section (15/47 versus 17/47, RR 1.1, 95% CI 0.6-2.0) were increased, and rates of instrumental birth were reduced (21/47 versus 17/47, RR 0.8, 95% CI 0.5-1.3). No evidence of increased harm for either mother or baby was found. The incidences of suspected delay (14%) and confirmed delay (11%) in labour were less than anticipated. Of those who did not go on to have delayed labour confirmed, all except one woman gave birth vaginally. CONCLUSIONS: A pilot trial assessing the efficacy of high-dose oxytocin was feasible, but uncertainty remains, highlighting the need for a large definitive trial. The implementation of national guidance of suspected and confirmed delay in labour is likely to reduce intervention.

The association between neurodevelopmental disability and economic outcomes during mid-childhood.

BACKGROUND: There is a paucity of evidence on the association between childhood disability and economic outcomes. This study estimates the economic costs and health utilities associated with neurodevelopmental impairment or serious neurodevelopmental disability during the 11th year of life. METHODS: Standardized tests of cognitive ability and clinical assessments of functional abilities were performed on participants of a whole population study of extremely preterm children and term-born controls (EPICure). Profiles of children's use of health, social and education services, and descriptions of their health status using the Health Utilities Index Mark 2 and Mark 3 health status classification systems, were extracted from detailed questionnaires completed by the main parent. Descriptive and multiple regression techniques were used to explore the association between neurodevelopmental impairment or serious neurodevelopmental disability and two sets of economic outcomes; economic costs and health utilities. RESULTS: Mean health and social service costs over the 12-month period were estimated at £577 [standard error (SE): £141] among children without neurodevelopmental impairment, £831 (£112) among children with a mild neurodevelopmental impairment, £1053 (£176) among children with a moderate neurodevelopmental impairment and £1662 (£316) among children with a severe neurodevelopmental impairment. Mean health and social service costs were estimated at £1223 (£157) and £695 (£92) among children with and without serious neurodevelopmental disability, respectively. After controlling for clinical and sociodemographic confounders, mild, moderate and severe neurodevelopment impairment increased health and social service costs by an average of £397 (95% CI: £86, £707; P= 0.012), £655 (95% CI: £167, £1144; P= 0.009) and £1065 (95% CI: -£113, £2243; P= 0.076), respectively. Cost differences were accentuated when broader public sector costs were considered. The mean (SE) Health Utilities Index Mark 3 multi-attribute utility score for the children with neurodevelopmental disability was 0.652 (0.039), compared with 0.923 (0.009) for children without neurodevelopmental disability, generating a mean difference in utility score of 0.272 (95% CI: 0.220, 0.323) that was statistically significant (P < 0.001). CONCLUSIONS: Our data should act as a significant new resource for economic analysts modelling the overall economic impact of childhood neurodevelopment impairment or disability or the cost-effectiveness of interventions targeted at neurodevelopmentally impaired or disabled children.

Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures.

Epilepsies affect at least 2% of the population at some time in life, and many forms have genetic determinants. We have found a mutation in a gene encoding a GABA(A) receptor subunit in a large family with epilepsy. The two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS). There is a recognized genetic relationship between FS and CAE, yet the two syndromes have different ages of onset, and the physiology of absences and convulsions is distinct. This suggests the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. We found that the mutation in GABRG2 (encoding the gamma2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.

Generation of an iPSC line (FINi001-A) from a girl with developmental and epileptic encephalopathy due to a heterozygous gain-of-function p.R1882Q variant in the voltage-gated sodium channel Nav1.2 protein encoded by the SCN2A gene.

A range of epilepsies, including the most severe group of developmental and epileptic encephalopathies (DEEs), are caused by gain-of-function variants in voltage-gated channels. Here we report the generation and characterisation of an iPSC cell line from the fibroblasts of a girl with early infantile DEE carrying heterozygous missense gain-of-function mutation (R1882Q) in Nav1.2(SCN2A) protein, using transient transfection with a single mRNA molecule. The established iPSC line displays typical human primed pluripotent stem cell characteristics: typical colony morphology and robust expression of pluripotency-associated marker genes, ability to give rise to derivatives of all three embryonic germ layers, and normal karyotype without any SNP array-detectable copy number variations. We anticipate that this iPSC line will be useful for the development of neuronal hyperactivity-caused human stem cell-based DEE models, advancing both understanding and potential therapy development for this debilitating condition.

Randomised controlled trial of analgesia for the management of acute severe pain from traumatic injury: study protocol for the paramedic analgesia comparing ketamine and morphine in trauma (PACKMaN).

BACKGROUND: Prehospital analgesia is often required after traumatic injury, currently morphine is the strongest parenteral analgesia routinely available for use by paramedics in the United Kingdom (UK) when treating patients with severe pain. This protocol describes a multi-centre, randomised, double blinded trial comparing the clinical and cost-effectiveness of ketamine and morphine for severe pain following acute traumatic injury. METHODS: A two arm pragmatic, phase III trial working with two large NHS ambulance services, with an internal pilot. Participants will be randomised in equal numbers to either (1) morphine or (2) ketamine by IV/IO injection. We aim to recruit 446 participants over the age of 16 years old, with a self-reported pain score of 7 or above out of 10. Randomised participants will receive a maximum of 20 mg of morphine, or a maximum of 30 mg of ketamine, to manage their pain. The primary outcome will be the sum of pain intensity difference. Secondary outcomes measure the effectiveness of pain relief and overall patient experience from randomisation to arrival at hospital as well as monitoring the adverse events, resource use and cost-effectiveness outcomes. DISCUSSION: The PACKMAN study is the first UK clinical trial addressing the clinical and cost-effectiveness of ketamine and morphine in treating acute severe pain from traumatic injury treated by NHS paramedics. The findings will inform future clinical practice and provide insights into the effectiveness of ketamine as a prehospital analgesia. TRIAL REGISTRATION: ISRCTN, ISRCTN14124474. Registered 22 October 2020, https://www.isrctn.com/ISRCTN14124474.

An online parenting intervention to prevent affective disorders in high-risk adolescents: the PIPA trial protocol.

BACKGROUND: Adolescent depression can place a young person at high risk of recurrence and a range of psychosocial and vocational impairments in adult life, highlighting the importance of early recognition and prevention. Parents/carers are well placed to notice changes in their child's emotional wellbeing which may indicate risk, and there is increasing evidence that modifiable factors exist within the family system that may help reduce the risk of depression and anxiety in an adolescent. A randomised controlled trial (RCT) of the online personalised 'Partners in Parenting' programme developed in Australia, focused on improving parenting skills, knowledge and awareness, showed that it helped reduce depressive symptoms in adolescents who had elevated symptom levels at baseline. We have adapted this programme and will conduct an RCT in a UK setting. METHODS: In total, 433 family dyads (parents/carers and children aged 11-15) will be recruited through schools, social media and parenting/family groups in the UK. Following completion of screening measures of their adolescent's depressive symptoms, parents/carers of those with elevated scores will be randomised to receive either the online personalised parenting programme or a series of online factsheets about adolescent development and wellbeing. The primary objective will be to test whether the personalised parenting intervention reduces depressive symptoms in adolescents deemed at high risk, using the parent-reported Short Mood & Feelings Questionnaire. Follow-up assessments will be undertaken at 6 and 15 months and a process evaluation will examine context, implementation and impact of the intervention. An economic evaluation will also be incorporated with cost-effectiveness of the parenting intervention expressed in terms of incremental cost per quality-adjusted life year gained. DISCUSSION: Half of mental health problems emerge before mid-adolescence and approximately three-quarters by mid-20s, highlighting the need for effective preventative strategies. However, few early interventions are family focused and delivered online. We aim to conduct a National Institute for Health and Care Research (NIHR) funded RCT of the online personalised 'Partners in Parenting' programme, proven effective in Australia, targeting adolescents at risk of depression to evaluate its effectiveness, cost-effectiveness and usability in a UK setting. TRIAL REGISTRATION {2A}: ISRCTN63358736 . Registered 18 September 2019.

Cost-effectiveness analysis of prostaglandin E2 gel for the induction of labour at term.

OBJECTIVE: To estimate the cost-effectiveness of prostaglandin E2 (dinoprostone) vaginal gel for the induction of labour at term from the perspective of the UK's National Health Service. DESIGN: Economic evaluation conducted as part of a randomised controlled trial. SETTING: Maternity department at a major teaching hospital in London, UK. POPULATION: A cohort of 165 pregnant women presenting as cephalic between 36(+6) and 41(+6) weeks of gestation, for whom induction of labour was deemed necessary. METHODS: Either 3-mg Prostin E2 vaginal tablets or 1- or 2-mg Prostin E2 vaginal gel were administered at 6-hourly intervals. MAIN OUTCOME MEASURES: Incremental cost per hour prevented between induction and delivery. The nonparametric bootstrap method was used to construct cost-effectiveness acceptability curves and estimate net benefits at alternative cost-effectiveness thresholds. RESULTS: Women receiving the gel accrued nonsignificantly higher costs (incremental cost £630; bootstrap 95% CI -£353, £2320; P = 0.43), and experienced a significantly reduced interval between induction and delivery (median of 1400 versus 1780 minutes; mean of 1711 versus 2765 minutes; P = 0.03). The incremental cost per hour prevented from induction of labour to delivery was estimated at £36. At a cost-effectiveness threshold of £100 per hour of care prevented, the probability that the gel is cost-effective was estimated at 0.83, and the mean net benefit to the health services was estimated at £1121 (bootstrap 95% CI -£1133, £3379). The results were sensitive to the inclusion of neonatal costs in the analysis and the value of the cost-effectiveness threshold. Notably, excluding neonatal costs increased the probability that the gel is cost-effective at a cost-effectiveness threshold of £100 per hour of care prevented to 0.99. CONCLUSIONS: This study suggests that prostaglandin E2 gel is probably more cost-effective than prostaglandin E2 tablets for the induction of labour at term. Given that the results are applicable to the general obstetric population requiring induction of labour at term, decision-makers should consider the likely economic impacts of their implementation.

Randomised placebo-controlled trial of outpatient (at home) cervical ripening with isosorbide mononitrate (IMN) prior to induction of labour--clinical trial with analyses of efficacy and acceptability. The IMOP study.

OBJECTIVE: To determine whether isosorbide mononitrate (IMN), self-administered vaginally by women at home, improves the process of induction of labour. DESIGN: Randomised double blind placebo-controlled trial. SETTING: Large UK maternity hospital. POPULATION OR SAMPLE: Nulliparous women with a singleton pregnancy, cephalic presentation > or = 37 weeks gestation, requiring cervical ripening prior to induction of labour. METHODS: IMN (n = 177) or placebo (n = 173) self-administered vaginally at home at 48, 32 and 16 hours prior to the scheduled time of admission for induction. MAIN OUTCOME MEASURES: Admission to delivery interval and women's experience of induction of labour. RESULTS: IMN did not shorten the admission to delivery interval as compared with placebo [mean difference of -1.6 hours (95% CI -5.1,1.9, P = 0.37)], despite being more effective than placebo in inducing a change in Bishop score [mean difference of 0.65 (95% CI 0.14,1.17, P = 0.013)]. While both groups found the overall experience of home treatment to be positive, (mean score of 3.8/10 +/- 2.3/10 for the IMN group, where 1 = extremely good and 10 = not at all good) women in the placebo group found it marginally more positive than those in the IMN group (just over half a unit on a 10-point scale, P = 0.043). There were no differences between the groups in the pain or anxiety experienced or willingness to take the treatment in a subsequent pregnancy. CONCLUSIONS: IMN self-administered vaginally at home does not shorten admission to delivery interval despite a significant effect on cervical ripeness assessed using the Bishop score. However, women report positive views on cervical ripening at home, and the setting deserves further investigation.

The cost-effectiveness of outpatient (at home) cervical ripening with isosorbide mononitrate prior to induction of labour.

OBJECTIVES: To assess the cost-effectiveness of outpatient (at home) cervical ripening with isosorbide mononitrate (IMN) prior to induction of labour. DESIGN: Economic evaluation was conducted alongside a randomised placebo controlled trial (the IMOP trial). SETTING: Large UK maternity hospital. POPULATION: A total of 350 nulliparous women with a singleton pregnancy, cephalic presentation > or = 37 weeks gestation, requiring cervical ripening prior to induction of labour. INTERVENTIONS: Isosorbide mononitrate (n = 177) or placebo (n = 173) self-administered vaginally at home at 48, 32 and 16 hours prior to the scheduled time of admission for induction. RESULTS: Mean health service costs between the period of randomisation and discharge for mother and infant were 1254.86 pound sterling in the IMN group and 1242.88 pound sterling in the placebo group, generating a mean cost difference of 11.98 pound sterling (bootstrap mean cost difference 12.86 pound sterling; 95%CI: -106.79 pound sterling, 129.39 pound sterling) that was not statistically significant (P = 0.842). The incremental cost per hour prevented from hospital admission to delivery was 7.53 pound sterling. At the notional willingness to pay threshold of 100 pound sterling per hour prevented from hospital admission to delivery, the probability that IMN is cost-effective was estimated at 0.67. This translated into a mean net monetary benefit of 98.13 pound sterling for each woman given IMN. CONCLUSIONS: Although the probability that IMN is cost-effective approaches 0.7 at seemingly low willingness to pay thresholds for an hour prevented from hospital admission to delivery, our results should be viewed in the light of the clinical findings from the IMOP trial.

Estimating neuronal conductance model parameters using dynamic action potential clamp.

BACKGROUND: Parameterization of neuronal membrane conductance models relies on data acquired from current clamp (CC) or voltage clamp (VC) recordings. Although the CC approach provides key information on a neuron's firing properties, it is often difficult to disentangle the influence of multiple conductances that contribute to the excitation properties of a real neuron. Isolation of a single conductance using pharmacological agents or heterologous expression simplifies analysis but requires extensive VC evaluation to explore the complete state behavior of the channel of interest. NEW METHOD: We present an improved parameterization approach that uses data derived from dynamic action potential clamp (DAPC) recordings to extract conductance equation parameters. We demonstrate the utility of the approach by applying it to the standard Hodgkin-Huxley conductance model although other conductance models could be easily incorporated as well. RESULTS: Using a fully simulated setup we show that, with as few as five action potentials previously recorded in DAPC mode, sodium conductance equation parameters can be determined with average parameter errors of less than 4% while action potential firing accuracy approaches 100%. In real DAPC experiments, we show that by "training" our model with five or fewer action potentials, subsequent firing lasting for several seconds could be predicted with ˜96% mean firing rate accuracy and 94% temporal overlap accuracy. COMPARISON WITH EXISTING METHODS: Our DAPC-based approach surpasses the accuracy of VC-based approaches for extracting conductance equation parameters with a significantly reduced temporal overhead. CONCLUSION: DAPC-based approach will facilitate the rapid and systematic characterization of neuronal channelopathies.

Cost-effectiveness of negative-pressure wound therapy in adults with severe open fractures of the lower limb: evidence from the WOLLF randomized controlled trial.

AIMS: The aim of this study was to estimate the cost-effectiveness of negative-pressure wound therapy (NPWT) in comparison with standard wound management after initial surgical wound debridement in adults with severe open fractures of the lower limb. PATIENTS AND METHODS: An economic evaluation was conducted from the perspective of the United Kingdom NHS and Personal Social Services, based on evidence from the 460 participants in the Wound Management of Open Lower Limb Fractures (WOLLF) trial. Economic outcomes were collected prospectively over the 12-month follow-up period using trial case report forms and participant-completed questionnaires. Bivariate regression of costs (given in £, 2014 to 2015 prices) and quality-adjusted life-years (QALYs), with multiple imputation of missing data, was conducted to estimate the incremental cost per QALY gained associated with NPWT dressings. Sensitivity and subgroup analyses were undertaken to assess the impacts of uncertainty and heterogeneity, respectively, surrounding aspects of the economic evaluation. RESULTS: The base case analysis produced an incremental cost-effectiveness ratio of £267 910 per QALY gained, reflecting higher costs on average (£678; 95% confidence interval (CI) -£1082 to £2438) and only marginally higher QALYS (0.002; 95% CI -0.054 to 0.059) in the NPWT group. The probability that NPWT is cost-effective in this patient population did not exceed 27% regardless of the value of the cost-effectiveness threshold. This result remained robust to several sensitivity and subgroup analyses. CONCLUSION: This trial-based economic evaluation suggests that NPWT is unlikely to be a cost-effective strategy for improving outcomes in adult patients with severe open fractures of the lower limb. Cite this article: Bone Joint J 2019;101-B:1392-1401.