Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial

Background Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. Methods Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. Findings The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. Interpretation Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia

Understanding the Use of Prostate Biopsy Among Men with Limited Life Expectancy in a Statewide Quality Improvement Collaborative

BACKGROUND: The potential harms of a prostate cancer (PCa) diagnosis may outweigh its benefits in elderly men. OBJECTIVE: To assess the use of prostate biopsy in men with limited life expectancy (LE) within the practices comprising the Michigan Urological Surgery Improvement Collaborative (MUSIC). DESIGN, SETTING, AND PARTICIPANTS: MUSIC is a consortium of 42 practices and nearly 85% of the urologists in Michigan. From July 2013 to October 2014, clinical data were collected prospectively for all men undergoing prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We calculated comorbidity-adjusted LE in men aged ≥66 yr and identified men with(limited LE) undergoing a first biopsy. Our LE calculator was not designed for men agedyr; thus these men were excluded. Multivariable models estimated the proportion of all biopsies performed for men with limited LE in each MUSIC practice, adjusting for differences in patient characteristics. We also evaluated what treatments, if any, these patients received. RESULTS AND LIMITATIONS: Among 3035 men aged ≥66 yr undergoing initial prostate biopsy, 60% had none of the measured comorbidities. Overall, 547 men (18%) had limited LE. Compared with men with a longer LE, these men had significantly higher prostate-specific antigen levels and abnormal digital rectal examination findings. The adjusted proportion of biopsies performed for men with limited LE ranged from 3.8% to 39% across MUSIC practices (p \u3c 0.001). PCa was diagnosed in 69% of men with limited LE; among this group, 74% received any active treatment. Of these men, 46% had high-grade cancer (Gleason score 8-10). CONCLUSIONS: Among a large and diverse group of urology practices, nearly 20% of prostate biopsies are performed in men with limited LE. These data provide useful context for quality improvement efforts aimed at optimizing patient selection for prostate biopsy. PATIENT SUMMARY: In this report, nearly 2 of every 10 men undergoing prostate biopsy had a life expectancy (LE)biopsy

Prophylactic antibiotics in the prevention of infection after operative vaginal delivery (ANODE): a multicentre randomised controlled trial.

BACKGROUND: Risk factors for maternal infection are clearly recognised, including caesarean section and operative vaginal birth. Antibiotic prophylaxis at caesarean section is widely recommended because there is clear systematic review evidence that it reduces incidence of maternal infection. Current WHO guidelines do not recommend routine antibiotic prophylaxis for women undergoing operative vaginal birth because of insufficient evidence of effectiveness. We aimed to investigate whether antibiotic prophylaxis prevented maternal infection after operative vaginal birth. METHODS: In a blinded, randomised controlled trial done at 27 UK obstetric units, women (aged ≥16 years) were allocated to receive a single dose of intravenous amoxicillin and clavulanic acid or placebo (saline) following operative vaginal birth at 36 weeks gestation or later. The primary outcome was confirmed or suspected maternal infection within 6 weeks of delivery defined by a new prescription of antibiotics for specific indications, confirmed systemic infection on culture, or endometritis. We did an intention-to-treat analysis. This trial is registered with ISRCTN, number 11166984, and is closed to accrual. FINDINGS: Between March 13, 2016, and June 13, 2018, 3427 women were randomly assigned to treatment: 1719 to amoxicillin and clavulanic acid, and 1708 to placebo. Seven women withdrew, leaving 1715 in the amoxicillin and clavulanic acid group and 1705 in the placebo groups. Primary outcome data were missing for 195 (6%) women. Significantly fewer women allocated to amoxicillin and clavulanic acid had a confirmed or suspected infection (180 [11%] of 1619) than women allocated to placebo (306 [19%] of 1606; risk ratio 0·58, 95% CI 0·49-0·69; p<0·0001). One woman in the placebo group reported a skin rash and two women in the amoxicillin and clavulanic acid reported other allergic reactions, one of which was reported as a serious adverse event. Two other serious adverse events were reported, neither was considered causally related to the treatment. INTERPRETATION: This trial shows benefit of a single dose of prophylactic antibiotic after operative vaginal birth and guidance from WHO and other national organisations should be changed to reflect this. FUNDING: NIHR Health Technology Assessment programme

The views of older women towards mammographic screening: a qualitative and quantitative study

Purpose: Mammographic screening has improved breast cancer survival in the screened age group. This improved survival has not been seen in older women (>70 years) where screening uptake is low. This study explores the views, knowledge and attitudes of older women towards screening. Methods: Women (>70) were interviewed about breast screening. Interview findings informed the development of a questionnaire which was sent to 1000 women (>70) to quantify their views regarding screening. Results: Twenty-six women were interviewed and a questionnaire designed. The questionnaire response rate was 48.3% (479/992). Over half (52.9%, 241/456) of respondents were unaware they could request mammography by voluntary self-referral and were unaware of how to arrange this. Most (81.5% 383/470) had not attended breast screening since turning 70. Most (75.6%, 343/454) felt screening was beneficial and would attend if invited. Most, (90.1%, 412/457) felt screening should be offered to all women regardless of age or health. Conclusions: There is a lack of knowledge about screening in older women. The majority felt that invitation to screening should be extended to the older age group regardless of age or health. The current under-utilised system of voluntary self referral is not supported by older women

The Birthplace in England national prospective cohort study: further analyses to enhance policy and service delivery decision-making for planned place of birth

Background: Evidence from the Birthplace in England Research Programme supported a policy of offering ‘low risk’ women a choice of birth setting, but a number of unanswered questions remained. Aims: This project aimed to provide further evidence to support the development and delivery of maternity services and inform women’s choice of birth setting: specifically, to explore maternal and organisational factors associated with intervention, transfer and other outcomes in each birth setting in ‘low risk’ and ‘higher risk’ women. Design: Five component studies using secondary analysis of the Birthplace prospective cohort study (studies 2–5) and ecological analysis of unit/NHS trust-level data (studies 1 and 5). Setting: Obstetric units (OUs), alongside midwifery units (AMUs), freestanding midwifery units (FMUs) and planned home births in England. Participants: Studies 1–4 focused on ‘low risk’ women with ‘term’ pregnancies planning vaginal birth in 43 AMUs (n = 16,573), in 53 FMUs (n = 11,210), at home in 147 NHS trusts (n = 16,632) and in a stratified, random sample of 36 OUs (n = 19,379) in 2008–10. Study 5 focused on women with pre-existing medical and obstetric risk factors (‘higher risk’ women). Main outcome measures: Interventions (instrumental delivery, intrapartum caesarean section), a measure of low intervention (‘normal birth’), a measure of spontaneous vaginal birth without complications (‘straightforward birth’), transfer during labour and a composite measure of adverse perinatal outcome (‘intrapartum-related mortality and morbidity’ or neonatal admission within 48 hours for > 48 hours). In studies 1 and 3, rates of intervention/maternal outcome and transfer were adjusted for maternal characteristics. Analysis: We used (a) funnel plots to explore variation in rates of intervention/maternal outcome and transfer between units/trusts, (b) simple, weighted linear regression to evaluate associations between unit/trust characteristics and rates of intervention/maternal outcome and transfer, (c) multivariable Poisson regression to evaluate associations between planned place of birth, maternal characteristics and study outcomes, and (d) logistic regression to investigate associations between time of day/day of the week and study outcomes. Results: Study 1 – unit-/trust-level variations in rates of interventions, transfer and maternal outcomes were not explained by differences in maternal characteristics. The magnitude of identified associations between unit/trust characteristics and intervention, transfer and outcome rates was generally small, but some aspects of configuration were associated with rates of transfer and intervention. Study 2 – ‘low risk’ women planning non-OU birth had a reduced risk of intervention irrespective of ethnicity or area deprivation score. In nulliparous women planning non-OU birth the risk of intervention increased with increasing age, but women of all ages planning non-OU birth experienced a reduced risk of intervention. Study 3 – parity, maternal age, gestational age and ‘complicating conditions’ identified at the start of care in labour were independently associated with variation in the risk of transfer in ‘low risk’ women planning non-OU birth. Transfers did not vary by time of day/day of the week in any meaningful way. The duration of transfer from planned FMU and home births was around 50–60 minutes; transfers for ‘potentially urgent’ reasons were quicker than transfers for ‘non-urgent’ reasons. Study 4 – the occurrence of some interventions varied by time of the day/day of the week in ‘low risk’ women planning OU birth. Study 5 – ‘higher risk’ women planning birth in a non-OU setting had fewer risk factors than ‘higher risk’ women planning OU birth and these risk factors were different. Compared with ‘low risk’ women planning home birth, ‘higher risk’ women planning home birth had a significantly increased risk of our composite adverse perinatal outcome measure. However, in ‘higher risk’ women, the risk of this outcome was lower in planned home births than in planned OU births, even after adjustment for clinical risk factors. Conclusions: Expansion in the capacity of non-OU intrapartum care could reduce intervention rates in ‘low risk’ women, and the benefits of midwifery-led intrapartum care apply to all ‘low risk’ women irrespective of age, ethnicity or area deprivation score. Intervention rates differ considerably between units, however, for reasons that are not understood. The impact of major changes in the configuration of maternity care on outcomes should be monitored and evaluated. The impact of non-clinical factors, including labour ward practices, staffing and skill mix and women’s preferences and expectations, on intervention requires further investigation. All women planning non-OU birth should be informed of their chances of transfer and, in particular, older nulliparous women and those more than 1 week past their due date should be advised of their increased chances of transfer. No change in the guidance on planning place of birth for ‘higher risk’ women is recommended, but research is required to evaluate the safety of planned AMU birth for women with selected relatively common risk factors. Funding: The National Institute for Health Research Health Services and Delivery Research programme

Perinatal and maternal outcomes in planned home and obstetric unit births in women at ‘higher risk’ of complications: secondary analysis of the Birthplace national prospective cohort study

Objective: To explore and compare perinatal and maternal outcomes in women at ‘higher risk’ of complications planning home versus obstetric unit (OU) birth. Design: Prospective cohort study. Setting: OUs and planned home births in England. Population: 8180 ‘higher risk’ women in the Birthplace cohort. Methods: We used Poisson regression to calculate relative risks adjusted for maternal characteristics. Sensitivity analyses explored possible effects of differences in risk between groups and alternative outcome measures. Main outcome measures: Composite perinatal outcome measure encompassing ‘intrapartum related mortality and morbidity’ (intrapartum stillbirth, early neonatal death, neonatal encephalopathy, meconium aspiration syndrome, brachial plexus injury, fractured humerus or clavicle) and neonatal admission within 48 hours for more than 48 hours. Two composite maternal outcome measures capturing intrapartum interventions/adverse maternal outcomes and straightforward birth. Results: The risk of ‘intrapartum related mortality and morbidity’ or neonatal admission for more than 48 hours was lower in planned home births than planned OU births [adjusted relative risks (RR) 0.50, 95% CI 0.31–0.81]. Adjustment for clinical risk factors did not materially affect this finding. The direction of effect was reversed for the more restricted outcome measure ‘intrapartum related mortality and morbidity’ (RR adjusted for parity 1.92, 95% CI 0.97–3.80). Maternal interventions were lower in planned home births. Conclusions: The babies of ‘higher risk’ women who plan birth in an OU appear more likely to be admitted to neonatal care than those whose mothers plan birth at home, but it is unclear if this reflects a real difference in morbidity. Rates of intrapartum related morbidity and mortality did not differ statistically significantly between settings at the 5% level but a larger study would be required to rule out a clinically important difference between the groups

Cancer symptom awareness and barriers to symptomatic presentation in England – Are we clear on cancer?

Background: Low cancer awareness may contribute to delayed diagnosis and poor cancer survival. We aimed to quantify socio-demographic differences in cancer symptom awareness and barriers to symptomatic presentation in the English population. Methods: Using a uniquely large data set (n=49?270), we examined the association of cancer symptom awareness and barriers to presentation with age, gender, marital status and socio-economic position (SEP), using logistic regression models to control for confounders. Results: The youngest and oldest, the single and participants with the lowest SEP recognised the fewest cancer symptoms, and reported most barriers to presentation. Recognition of nine common cancer symptoms was significantly lower, and embarrassment, fear and difficulties in arranging transport to the doctor’s surgery were significantly more common in participants living in the most deprived areas than in the most affluent areas. Women were significantly more likely than men to both recognise common cancer symptoms and to report barriers. Women were much more likely compared with men to report that fear would put them off from going to the doctor. Conclusions: Large and robust socio-demographic differences in recognition of some cancer symptoms, and perception of some barriers to presentation, highlight the need for targeted campaigns to encourage early presentation and improve cancer outcomes

Distributed situation awareness in dynamic systems: Theoretical development and application of an ergonomics methodology

The purpose of this paper is to propose foundations for a theory of situation awareness based on the analysis of interactions between agents (i.e., both human and non-human) in subsystems. This approach may help promote a better understanding of technology-mediated interaction in systems, as well as helping in the formulation of hypotheses and predictions concerning distributed situation awareness. It is proposed that agents within a system each hold their own situation awareness which may be very different from (although compatible with) other agents. It is argued that we should not always hope for, or indeed want, sharing of this awareness, as different system agents have different purposes. This view marks situation awareness as a 1 dynamic and collaborative process that binds agents together on tasks on a moment-by-moment basis. Implications of this viewpoint for development of a new theory of, and accompanying methodology for, distributed situation awareness are offered

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)