Immune and metabolic markers for identifying and investigating severe Coronavirus disease and Sepsis in children and young people (pSeP/COVID ChYP study): protocol for a prospective cohort study.

INTRODUCTION: Early recognition and appropriate management of paediatric sepsis are known to improve outcomes. A previous system's biology investigation of the systemic immune response in neonates to sepsis identified immune and metabolic markers that showed high accuracy for detecting bacterial infection. Further gene expression markers have also been reported previously in the paediatric age group for discriminating sepsis from control cases. More recently, specific gene signatures were identified to discriminate between COVID-19 and its associated inflammatory sequelae. Through the current prospective cohort study, we aim to evaluate immune and metabolic blood markers which discriminate between sepses (including COVID-19) from other acute illnesses in critically unwell children and young persons, up to 18 years of age. METHODS AND ANALYSIS: We describe a prospective cohort study for comparing the immune and metabolic whole-blood markers in patients with sepsis, COVID-19 and other illnesses. Clinical phenotyping and blood culture test results will provide a reference standard to evaluate the performance of blood markers from the research sample analysis. Serial sampling of whole blood (50 µL each) will be collected from children admitted to intensive care and with an acute illness to follow time dependent changes in biomarkers. An integrated lipidomics and RNASeq transcriptomics analyses will be conducted to evaluate immune-metabolic networks that discriminate sepsis and COVID-19 from other acute illnesses. This study received approval for deferred consent. ETHICS AND DISSEMINATION: The study has received research ethics committee approval from the Yorkshire and Humber Leeds West Research Ethics Committee 2 (reference 20/YH/0214; IRAS reference 250612). Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites. TRIAL REGISTRATION NUMBER: NCT04904523.

Immune-metabolic adaptations in pregnancy: A potential stepping-stone to sepsis.

Physiological shifts during pregnancy predispose women to a higher risk of developing sepsis resulting from a maladapted host-response to infection. Insightful studies have delineated subtle point-changes to the immune system during pregnancy. Here, we present an overlay of these point-changes, asking what changes and when, at a physiological, cellular, and molecular systems-level in the context of sepsis. We identify distinct immune phases in pregnancy delineated by placental hormone-driven changes in homeostasis setpoints of the immune and metabolic systems that subtly mirrors changes observed in sepsis. We propose that pregnancy immune-metabolic setpoint changes impact feedback thresholds that increase risk for a maladapted host-response to infection and thus act as a stepping-stone to sepsis. Defining maternal immune-metabolic setpoint changes is not only vital for tailoring the right diagnostic tools for early management of maternal sepsis but will facilitate an unravelling of the pathophysiological pathways that predispose an individual to sepsis.

mSep: investigating physiological and immune-metabolic biomarkers in septic and healthy pregnant women to predict feto-maternal immune health - a prospective observational cohort study protocol.

INTRODUCTION: Maternal sepsis remains a leading cause of death in pregnancy. Physiological adaptations to pregnancy obscure early signs of sepsis and can result in delays in recognition and treatment. Identifying biomarkers that can reliably diagnose sepsis will reduce morbidity and mortality and antibiotic overuse. We have previously identified an immune-metabolic biomarker network comprising three pathways with a >99% accuracy for detecting bacterial neonatal sepsis. In this prospective study, we will describe physiological parameters and novel biomarkers in two cohorts-healthy pregnant women and pregnant women with suspected sepsis-with the aim of mapping pathophysiological drivers and evaluating predictive biomarkers for diagnosing maternal sepsis. METHODS AND ANALYSIS: Women aged over 18 with an ultrasound-confirmed pregnancy will be recruited to a pilot and two main study cohorts. The pilot will involve blood sample collection from 30 pregnant women undergoing an elective caesarean section. Cohort A will follow 100 healthy pregnant women throughout their pregnancy journey, with collection of blood samples from participants at routine time points in their pregnancy: week 12 'booking', week 28 and during labour. Cohort B will follow 100 pregnant women who present with suspected sepsis in pregnancy or labour and will have at least two blood samples taken during their care pathway. Study blood samples will be collected during routine clinical blood sampling. Detailed medical history and physiological parameters at the time of blood sampling will be recorded, along with the results of routine biochemical tests, including C reactive protein, lactate and white blood cell count. In addition, study blood samples will be processed and analysed for transcriptomic, lipidomic and metabolomic analyses and both qualitative and functional immunophenotyping. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Wales Research Ethics Committee 2 (SPON1752-19, 30 October 2019). TRIAL REGISTRATION NUMBER: NCT05023954.

Synthetic osmotic dilators (Dilapan-S) or dinoprostone vaginal inserts (Propess) for inpatient induction of labour: A UK cost-consequence model.

OBJECTIVE: To estimate the costs of synthetic osmotic dilators (Dilapan-S) compared to dinoprostone vaginal inserts (Propess) for inpatient induction of labour (IOL). STUDY DESIGN: A population-level, Markov model-based cost-consequence analysis was developed to compare the impact of using Dilapan-S versus Propess. The time horizon was modelled from admission to birth. The target population was women requiring inpatient IOL from 37 weeks with an unfavourable cervix in the UK. Mean population characteristics reflected those of the SOLVE (NCT03001661) trial. No patient data were included in this analysis. The care pathways and staff workload were modelled using data from the SOLVE trial and clinical experience. Cost and clinical inputs were sourced from the SOLVE trial and peer-reviewed literature. Costs were inflated to 2020 British pounds (GBP, £). Outcomes were reported as an average per woman for total costs and required staff time (minutes) from admission for IOL until birth. The model robustness was assessed using a probabilistic, multivariate sensitivity analysis of 2,000 simulations with results presented as the median (interquartile range, IQR). RESULTS: Dilapan-S was cost neutral compared to Propess. Midwife and obstetrician times were decreased by 146 min (-11%) and 11 min (-54%), respectively. Sensitivity analysis showed that in 78% of simulations, use of Dilapan-S reduced midwife time with a median of -160 min (IQR -277 to -24 min). Costs were reduced in 54% of simulations (median -£33, IQR -£319 to £282). CONCLUSIONS: The model indicates that adoption of Dilapan-S is likely to be cost-neutral and reduce staff workload in comparison to Propess. Results require support from real-world data and further exploration of Dilapan-S is to be encouraged.

nSeP: immune and metabolic biomarkers for early detection of neonatal sepsis-protocol for a prospective multicohort study.

INTRODUCTION: Diagnosing neonatal sepsis is heavily dependent on clinical phenotyping as culture-positive body fluid has poor sensitivity, and existing blood biomarkers have poor specificity.A combination of machine learning, statistical and deep pathway biology analyses led to the identification of a tripartite panel of biologically connected immune and metabolic markers that showed greater than 99% accuracy for detecting bacterial infection with 100% sensitivity. The cohort study described here is designed as a large-scale clinical validation of this previous work. METHODS AND ANALYSIS: This multicentre observational study will prospectively recruit a total of 1445 newborn infants (all gestations)-1084 with suspected early-or late-onset sepsis, and 361 controls-over 4 years. A small volume of whole blood will be collected from infants with suspected sepsis at the time of presentation. This sample will be used for integrated transcriptomic, lipidomic and targeted proteomics profiling. In addition, a subset of samples will be subjected to cellular phenotype and proteomic analyses. A second sample from the same patient will be collected at 24 hours, with an opportunistic sampling for stool culture. For control infants, only one set of blood and stool sample will be collected to coincide with clinical blood sampling. Along with detailed clinical information, blood and stool samples will be analysed and the information will be used to identify and validate the efficacy of immune-metabolic networks in the diagnosis of bacterial neonatal sepsis and to identify new host biomarkers for viral sepsis. ETHICS AND DISSEMINATION: The study has received research ethics committee approval from the Wales Research Ethics Committee 2 (reference 19/WA/0008) and operational approval from Health and Care Research Wales. Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites. TRIAL REGISTRATION NUMBER: NCT03777670.

Falling caesarean section rate and improving intra-partum outcomes: a prospective cohort study.

OBJECTIVE: To evaluate caesarean section (CS) rates and moderate to severe hypoxaemic ischaemic encephalopathy (HIE) rates with other core intra-partum outcomes following reconfiguration of maternity services in Cardiff, South Wales, UK. DESIGN: Cohort study of births from 2006 to 2015. SETTINGS: A University tertiary referral centre for foetal and maternal medicine with 6000 births/year, University Hospital of Wales, United Kingdom. METHOD: Data relating to births from 1 January 2006 to 31 December 2015 were extracted from the computerized maternity database on a yearly basis. Case notes of all mothers and babies for the same duration were hand searched for documentation of HIE. HIE data was also collected prospectively by neonatologist (SC) and obstetrician (PA). MAIN OUTCOME MEASURES: Incidence of caesarean section births, babies with moderate to severe HIE, instrumental vaginal births, obstetric anal sphincter injuries (OASIS) associated with instrumental delivery, and major post-partum haemorrhage (MPPH) of 2500 mL or more. RESULTS: During this 10-year period, a downward trend in emergency CS rate was seen from 15.6% in 2006 to 10.5% in 2015, reducing total CS rate from 25.5% in 2006 to 21.2% in 2015. A downward trend in the incidence of moderate and severe HIE was seen over the same period. There was an increase in operative vaginal births (OVB) from 12.8% to 15%. The rate of spontaneous vaginal births (SVB) remained stable. The incidence of OASIS remained constant and MPPH rate has fallen. CONCLUSIONS: Following amalgamation of two medium sized obstetric units and the opening of a Midwifery Led Unit (MLU), core intrapartum outcomes have improved. Contributing factors are the introduction of regular multidisciplinary training with enhanced team working, compulsory education for obstetricians and midwives on cardiotocograph (CTG) interpretation, increased consultant presence on delivery suite, robust risk management systems and broad multidisciplinary agreement on clinical guidelines promoting vaginal birth.

Successful in vitro fertilization pregnancy following magnetic resonance-guided focused ultrasound surgery for uterine fibroids.

We describe an in vitro fertilization (IVF) pregnancy and delivery after magnetic resonance-guided focused ultrasound (MRgFUS) for a symptomatic uterine fibroid. A 45-year-old para 0 + 1, with four previous failed IVF treatments underwent MRgFUS for a single anterior wall fibroid causing intra-cavitary distortion and conceived after the first IVF cycle 10 months following the procedure. The patient received shared antenatal care. She was admitted in spontaneous labor at term but delivered by emergency cesarean section a healthy male infant. We describe the first IVF pregnancy following MRgFUS for a symptomatic fibroid.

A novel method to aid in the visualisation and treatment of uterine fibroids with MRgFUS in patients with abdominal scars.

The purpose of this research was to identify a method for performing Magnetic Resonance Imaging Guided Focused Ultrasound Surgery (MRgFUS) of symptomatic uterine fibroids in patients with abdominal scars, by visualisation of these scars on MR images. 25 patients who presented with treatable symptomatic uterine fibroids and having transverse abdominal scars were treated with MRgFUS. A solution containing MRI contrast paramagnetic iron oxide particles was used to demark the skin surface scar tissue on the treatment planning MR images. During treatment, the focused ultrasound energy was steered around the scar based on its enhanced visual location. After the treatment, contrast enhanced MR images were acquired for immediate results evaluation. Adverse events and fibroid related symptoms were captured during the 6-months follow up period. All the women were treated with no complications. No episodes of skin burns, ulceration or skin redness were reported. The post-treatment contrast-enhanced MR images showed an average fibroid non-perfused volume ratio of 64%. At their 6-month follow-up, 92% of the patients reported a clinical improvement. Using paramagnetic iron oxide solution to highlight transverse abdominal scars helps in their identification on MR images, thereby enabling the operator to avoid scars and facilitating the treatment of women who were previously excluded.

Patient suitability for magnetic resonance guided focused ultrasound surgery of uterine fibroids.

OBJECTIVE: To assess selection criteria used to determine eligibility for magnetic resonance-guided focused ultrasound surgery (MRgFUS) for the treatment of symptomatic uterine fibroids; to assess the percentage of patients suitable for MRgFUS. STUDY DESIGN: A retrospective analysis of 144 patients seeking minimally invasive treatment options for symptomatic uterine fibroids at a single treatment center. Clinical eligibility for MRgFUS was assessed at a gynecology clinic by a Gynecology research fellow trained in the procedure and suitability was assessed by magnetic resonance imaging. Several techniques were used to mitigate against factors that are contra-indications for MRgFUS. RESULTS: 100% of patients interested in MRgFUS were deemed clinically eligible for the procedure and 74% were deemed technically suitable to proceed with treatment. CONCLUSIONS: Mitigation techniques allow for less restrictive MRgFUS selection criteria for treatment for symptomatic uterine fibroids. These less restrictive criteria are expected to expand the pool of patients for whom MRgFUS is a viable treatment option for uterine fibroid symptoms.