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Abstract The construction of conjugated covalent organic frameworks (COFs) with strong C–C bond linkage remains a big challenge. Herein, we report a new strategy by using an oxidative C–C coupling reaction between electron-rich pyrrole rings at a liquid–liquid interface. Two threefold symmetric monomers containing three terminal pyrrole units were tested, and both gave two-dimensional conjugated COF films with good crystallinity. The bipyrrole units in the as-formed COFs are partially doped, which can be reduced to the neutral form by hydrazine and redoped by I2 vapor. The I2-doped films showed high conductivity (1.35 S/m). Meanwhile, the unpaired electrons exhibited moderate interlayer antiferromagnetic coupling.

Teck Yee Wong, David Koh, Andrew Wee, Vivian Ng, Yong Tat Koh, Zhenjie Sum, Gerald KohDepartment of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeBackground: Salivary eosinophil cationic protein (ECP) level has the potential to be an assessment tool for asthma. Its measurement is not well-established and needs standardization. We studied how passive drool (PD) and two commercial devices, Salivette® (cotton-based device) and Sorbette® (cellulose–cotton-based-device), may affect ECP levels during collection among healthy subjects.Methods: Study I (n = 10) involved direct sampling of healthy adult subjects with Salivette® and Sorbette®. Study II (n = 33) involved ‘indirect’ sampling of previously collected PD by both devices.Results: In study I, ECP levels were detected in all PD samples but only in three with Sorbette® and none with Salivette® (collection order: PD, Sorbette® and Salivette®). We changed the order of collection (Salivette®, Sorbette®, PD) and the results were similar (ECP levels detected in all PD samples, three with Sorbette® and only one with Salivette®). In study II, ECP levels in saliva collected by PD was 12.8 μg/L (median) and using Sorbette® and Salivette® were < 2.0 μg/L and 3.4 μg/L respectively (p

The land planarian Platydemus manokwari de Beauchamp, 1963 or “New Guinea flatworm” is a highly invasive species, mainly in the Pacific area, and recently in Europe (France). We report specimens from six additional countries and territories: New Caledonia (including mainland and two of the Loyalty Islands, Lifou and Maré), Wallis and Futuna Islands, Singapore, Solomon Islands, Puerto Rico, and Florida, USA. We analysed the COI gene (barcoding) in these specimens with two sets of primers and obtained 909 bp long sequences. In addition, specimens collected in Townsville (Australia) were also sequenced. Two haplotypes of the COI sequence, differing by 3.7%, were detected: the “World haplotype” found in France, New Caledonia, French Polynesia, Singapore, Florida and Puerto Rico; and the “Australian haplotype” found in Australia. The only locality with both haplotypes was in the Solomon Islands. The country of origin of Platydemus manokwari is New Guinea, and Australia and the Solomon Islands are the countries closest to New Guinea from which we had specimens. These results suggest that two haplotypes exist in the area of origin of the species, but that only one of the two haplotypes (the “World haplotype”) has, through human agency, been widely dispersed. However, since P. manokwari is now recorded from 22 countries in the world and we have genetic information from only 8 of these, with none from New Guinea, this analysis provides only partial knowledge of the genetic structure of the invasive species. Morphological analysis of specimens from both haplotypes has shown some differences in ratio of the genital structures but did not allow us to interpret the haplotypes as different species. The new reports from Florida and Puerto Rico are firsts for the USA, for the American continent, and the Caribbean. P. manokwari is a known threat for endemic terrestrial molluscs and its presence is a matter of concern. While most of the infected territories reported until now were islands, the newly reported presence of the species in mainland US in Florida should be considered a potential major threat to the whole US and even the Americas.

Abstract Background Understanding the aetiological organisms causing maternal infections is crucial to inform antibiotic treatment guidelines, but such data are scarce from Sub-Saharan Africa (SSA). We performed this systematic review and meta-analysis to address this gap. Methods Microbiologically confirmed maternal infection data were collected from PubMed, Embase, and African Journals online databases. The search strategy combined terms related to bacterial infection, pregnancy, postnatal period, observational studies, SSA. Exclusion criteria included colonization, asymptomatic infection, and screening studies. Pooled proportions for bacterial isolates and antimicrobial resistance (AMR) were calculated. Quality and completeness of reporting were assessed using the Newcastle–Ottawa and STROBE checklists. Findings We included 14 papers comprising data from 2,575 women from four sources (blood, urine, surgical wound and endocervical). Mixed-growth was commonly reported at 17% (95% CI: 12%-23%), E. coli from 11%(CI:10%-12%), S. aureus from 5%(CI: 5%-6%), Klebsiella spp. at 5%(CI: 4%- 5%) and Streptococcus spp. at 2%(CI: 1%-2%). We observed intra-sample and inter-sample heterogeneity between 88–92% in all meta-analyses. AMR rates were between 19% -77%, the highest with first-line beta-lactam antibiotics. Convenience sampling, and limited reporting of laboratory techniques were areas of concern. Interpretation We provide a comprehensive summary of microbial aetiology of maternal infections in SSA and demonstrate the paucity of data available for this region. We flag the need to review the current local and international empirical treatment guidelines for maternal bacterial infections in SSA because there is high prevalence of AMR among common causative bacteria. Funding This research was supported by the NIHR-Professorship/NIHR300808 and the Wellcome-Strategic-award /206545/Z/17/Z. Trial registration Prospero ID CRD42021238515.

Abstract Background Patient-Reported Outcomes or Experience Measures (PROMS / PREMS) are routinely used in clinical studies to assess participants’ views and experiences of trial interventions and related quality of life. Purely quantitative approaches lack the necessary detail and flexibility to understand the real-world impact of study interventions on participants, according to their own priorities. Conversely, purely qualitative assessments are time consuming and usually restricted to a small, possibly unrepresentative, sub-sample. This paper, which reports a pilot study within a randomised controlled trial of induction of labour, reports the feasibility, and acceptability of the Participant-Generated Experience and Satisfaction (PaGES) Index, a new mixed qualitative / quantitative PREM tool. Methods The single-sheet PaGES Index was completed by hypertensive pregnant women in two hospitals in Nagpur, India before and after taking part in the ‘Misoprostol or Oxytocin for Labour Induction’ (MOLI) randomised controlled trial. Participants recorded aspects of the impending birth they considered most important, and then ranked them. After the birth, participants completed the PaGES Index again, this time also scoring their satisfaction with each item. Forms were completed on paper in the local language or in English, supported by Research Assistants. Following translation (when needed), responses were uploaded to a REDCap database, coded in Excel and analysed thematically. A formal qualitative evaluation (qMOLI) was also conducted to obtain stakeholder perspectives of the PaGES Index and the wider trial. Semi-structured interviews were conducted with participants, and focus groups with researchers and clinicians. Data were managed using NVivo 12 software and analysed using the framework approach. Results Participants and researchers found the PaGES Index easy to complete and administer; mothers valued the opportunity to speak about their experience. Qualitative analysis of the initial 68 PaGES Index responses identified areas of commonality and difference among participants and also when comparing antenatal and postnatal responses. Theme citations and associated comments scores were fairly stable before and after the birth. The qMOLI phase, comprising 53 one-to-one interviews with participants and eight focus groups involving 83 researchers and clinicians, provided support that the PaGES Index was an acceptable and even helpful means of capturing participant perspectives. Conclusions Subjective participant experiences are an important aspect of clinical trials. The PaGES Index was found to be a feasible and acceptable measure that unites qualitative research’s explanatory power with the comparative power of quantitative designs. It also offers the opportunity to conduct a before-and-after evaluation, allowing researchers to examine the expectations and actual experiences of all clinical trial participants, not just a small sub-sample. This study also shows that, with appropriate research assistant input, the PaGES Index can be used in different languages by participants with varying literacy levels. Trial registration Clinical Trials.gov (21/11/2018) (NCT03749902).

Objective Trial legislation enables research to be conducted without prior consent (RWPC) in emergency situations, yet this approach has rarely been used in time-critical obstetric trials. This study explored views and experiences of antenatal recruitment and consent and RWPC in an emergency intrapartum randomised clinical trial.Design Embedded, mixed-methods study within a trial, involving questionnaires, recorded recruitment discussions, interviews and focus groups in the first 13 months of trial recruitment (December 2020–January 2022).Setting COPE is a double-blind randomised controlled trial, comparing the effectiveness of carboprost or oxytocin as first-line treatment of postpartum haemorrhage.Participants Two hundred and eighty-six people (190 women/96 birth partners), linked to 198/380 (52%) COPE recruits participated in the embedded study. Of these, 272 completed a questionnaire (178 women/94 birth partners), 22 were interviewed (19 women/3 birth partners) and 16 consent discussions with 12 women were recorded. Twenty-seven staff took part in three focus groups and nine staff were interviewed.Results Participants recommended that information about the study should be more accessible antenatally for those who wish to be informed. Most women and staff did not think it would be appropriate to seek consent during pregnancy or early labour as it may cause ‘unnecessary panic’ and lead to research waste, as most women would not become eligible. There was support for the use of RWPC as COPE interventions are used in standard clinical practice and viewed as low risk. Women who were approached about the trial while having a postpartum haemorrhage also supported RWPC as they could not recall research discussions.Conclusions Findings support the use of RWPC for time-critical interventions, and raise questions about the appropriateness of other commonly used consent pathways, including antenatal consent and verbal assent.

Women are advised to optimise weight before pregnancy. However, many are either already living with overweight or obesity prior to becoming pregnant, increasing the risks for adverse outcomes. Health care professionals (HCP) are responsible for advising women of risks throughout and following pregnancy. However, midwives often find broaching the conversation around maternal obesity difficult. This study explored the experiences of pregnant women living with obesity in accessing antenatal care. Seventeen women completed a semi-structured interview. Transcripts were analysed thematically. Four themes were developed: 1) antenatal care is inconsistent, 2) additional support is needed, 3) women feel judged about their weight, and 4) weight cycling is highly prevalent. Findings suggest that pregnant women living with obesity often experience weight bias from HCPs, feel judged because of their weight and are left feeling confused and overlooked. Women reported inconsistencies in advice and care offered and acknowledged a lack of continuity of care throughout pregnancy. We call for an urgent need for further multidisciplinary training to address the concerns, experiences and needs of pregnant women living with obesity.

Abstract Objective To compare body composition between patients with psoriatic disease (PsD), including cutaneous psoriasis (PsO) and psoriatic arthritis (PsA), and controls, and to explore associations between disease activity and measures of function and metabolic derangement. Methods Body composition was assessed by air displacement plethysmography (ADP) and MRI-derived fat segmentation using an automated pipeline (FatSegNet). Function was assessed by Health Assessment Questionnaire (HAQ) and metabolic status by fasting lipid profile, insulin and adiponectin. Active and inactive PsO and PsA were defined by body surface area (BSA) and Psoriasis Area Severity Index (PASI) and minimal disease activity (MDA), respectively. Results Thirty patients (median disease duration 15 years; median age 52 years) and 30 BMI-matched controls were enrolled. Compared with controls, all MRI-derived body composition parameters—whole-body volume, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), abdominal adipose tissue (AAT), VAT/AAT and VAT/SAT—were higher in the PsD group, specifically, those with active disease. Body mass, body fat, whole-body volume and whole-body VAT were correlated with higher triglycerides, cholesterol:HDL (high-density lipoprotein), insulin resistance and lower adiponectin as well as higher HAQ and lower MDA. Conclusions In this pilot study, patients with PsD revealed excessive total adipose tissue and a greater volume of metabolically unfavourable ectopic fat, including VAT, compared with BMI-matched controls, which also correlated with HAQ, disease activity and overall dysmetabolism. We also provide the first evidence in patients with PsD for the clinical application of FatSegNet: a novel, automated and rapid deep learning pipeline for providing accurate MRI-based measurement of fat segmentation. Our findings suggest the need for a more integrated approach to the management of PsD, which considers both the metabolic and inflammatory burden of disease. More specifically, visceral fat is a surrogate marker of uncontrolled PsD and may be an important future target for both pharmacological and lifestyle interventions.

Abstract Background Infections are one of the leading causes of death in the neonatal period. This trial aims to evaluate if the provision of alcohol-based hand rub (ABHR) to pregnant women for postnatal household use prevents severe infections (including sepsis, diarrhoea, pneumonia, or death) among infants during the first three postnatal months. Methods Through a cluster-randomised trial in eastern Uganda, 72 clusters are randomised in a 2-arm design with rural villages as units of randomisation. We estimate to include a total of 5932 pregnant women at 34 weeks of gestation. All women and infants in the study are receiving standard antenatal and postnatal care. Women in the intervention group additionally receive six litres of ABHR and training on its use. Research midwives conduct follow-up visits at participants’ homes on days 1, 7, 28, 42, and 90 after birth and telephone calls on days 14, 48, and 60 to assess the mother and infant for study outcomes. Primary analyses will be by intention to treat. Discussion This study will provide evidence on the effectiveness of a locally available and low-cost intervention in preventing neonatal sepsis and early infant infections. If ABHR is found effective, it could be implemented by adding it to birthing kits. Trial registration Pan African Clinical Trial Registry, PACTR202004705649428. Registered 1 April 2020, https://pactr.samrc.ac.za/ .

Objectives To explore the events perceived as traumatic by obstetricians and gynaecologists (O&G), and to examine factors contributing to the perception of trauma.Design Mixed methods: cross-sectional survey and in-depth interviews.Sample and setting Fellows, members and trainees of the Royal College of Obstetricians and Gynaecologists (RCOG).Methods An online survey was distributed to 6300 fellows (May–June 2017), members and trainees of RCOG; 1095 (17%) completed surveys were returned. Of these, 728 (66%) reported work-related trauma experience, with 525 providing a brief description of an event. Forty-three participants with trauma experience were purposively sampled and completed an in-depth interview (October 2017–March 2018), which were analysed using Template Analysis. Information regarding the scale and impact of trauma experience is presented elsewhere. The present analysis provides new information describing the events and perceptions of why events were traumatic.Primary outcome measures The nature of traumatic events in this clinical setting, taken from survey descriptions of perceived traumatic events and information from the in-depth interviews.Results Events perceived as traumatic by O&G were similar between consultants, trainees and other RCOG members no longer working in O&G. Maternal or neonatal death/stillbirth, haemorrhage and events involving a difficult delivery were most frequently reported. Sudden and unpredictable events, perceived preventability, acute sensory experiences and high emotionality contributed to trauma perception. Respondents’ trauma was compounded by an absence of support, involvement in investigation procedures and pre-existing relationships with a recipient of care.Conclusions Identification of events most likely to be perceived as traumatic, and wider circumstances contributing to the perception of trauma, provide a basis on which to focus preventative and supportive strategies for O&G. Training on the nature of traumatic events, self-help for early stress responses, processing support and rapid access to trauma-focused psychological input (where required) are needed.

Abstract Background Every year approximately 30,000 women die from hypertensive disease in pregnancy. Magnesium sulphate and anti-hypertensives reduce morbidity, but delivery is the only cure. Low dose oral misoprostol, a prostaglandin E1 analogue, is a highly effective method for labour induction. Usually, once active labour has commenced, the misoprostol is replaced with an intravenous oxytocin infusion if ongoing stimulation is required. However, some studies have shown that oral misoprostol can be continued into active labour, a simpler and potentially more acceptable protocol for women. To date, these two protocols have never been directly compared. Methods This pragmatic, open-label, randomised trial will compare a misoprostol alone labour induction protocol with the standard misoprostol plus oxytocin protocol in three Indian hospitals. The study will recruit 520 pregnant women being induced for hypertensive disease in pregnancy and requiring augmentation after membrane rupture. Participants will be randomised to receive either further oral misoprostol 25mcg every 2 h, or titrated intravenous oxytocin. The primary outcome will be caesarean birth. Secondary outcomes will assess the efficacy of the induction process, maternal and fetal/neonatal complications and patient acceptability. This protocol (version 1.04) adheres to the SPIRIT checklist. A cost-effectiveness analysis, situational analysis and formal qualitative assessment of women’s experience are also planned. Discussion Avoiding oxytocin and continuing low dose misoprostol into active labour may have a number of benefits for both women and the health care system. Misoprostol is heat stable, oral medication and thus easy to store, transport and administer; qualities particularly desirable in low resource settings. An oral medication protocol requires less equipment (e.g. electronic infusion pumps) and may free up health care providers to assist with other aspects of the woman’s care. The simplicity of the protocol may also help to reduce human errors associated with the delivery of intravenous infusions. Finally, women may prefer to be mobile during labour and not restricted by an intravenous infusion. There is a need, therefore, to assess whether augmentation using oral misoprostol is superior clinically and economically to the standard protocol of intravenous oxytocin. Trial registration Clinical Trials.gov, NCT03749902 , registered on 21st Nov 2018.

Plain language summary During the late stages of childbirth, complications can occur which require rapid birth of the baby. This can be facilitated with instruments (usually forceps or a suction cup) or by surgery (caesarean section). In some circumstances, instrumental birth (also termed assisted vaginal delivery, AVD) may be a better option than caesarean section. AVD requires practitioners to develop skills, competence and expertise in the procedure. Our aim for this review was to examine practitioners’, funders’ and policy makers’ views about competence and expertise in AVD, how they can best gain this, the barriers and facilitators to implementing training packages, and their views, opinions and perspectives of their training. We included 27 studies (published 1985–2020), mostly from high-income countries. We had moderate confidence on one findings statement, with the rest assessed with low confidence. We found that practitioners valued extra training in AVD, observing others using the different instruments, and opportunities for clinical supervision, mentorship to gain experience, competence and expertise. We also found that, from the practitioners’ perspective, competence encompasses a number of inter-related skill sets; non-technical skills (e.g. effective communication with the labouring woman), broad clinical skills (e.g. capacity to assess the whole clinical picture) and technical instrumental skills (e.g. correct application of a vacuum cup to the fetal head, or capacity to turn the baby so it is in the right position). Practitioners also identified a number of barriers and facilitators that supported (or did not support) their training needs and development.

Abstract Background Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality. Many trials assessing interventions to prevent PPH base their data on low risk women. It is important to consider the impact data collection methods may have on these results. This review aims to assess trials of PPH prophylaxis by grading trials according to the degree of risk status of the population enrolled in these trials and identify differences in the PPH rates of low risk and high risk populations. Methods Systematic review and meta-analysis using a random-effects model. Trials were identified through CENTRAL. Trials were assessed for eligibility then graded according to antenatal risk factors and method of birth into five grades. The main outcomes were overall trial rate of minor PPH (blood loss ≥500 ml) and major PPH (> 1000 ml) and method of determining blood loss (estimated/measured). Results There was no relationship between minor or major PPH rate and risk grade (Kruskal-Wallis: minor - T = 0.92, p = 0.82; major - T = 0.91, p = 0.92). There was no difference in minor or major PPH rates when comparing estimation or measurement methods (Mann-Whitney: minor - U = 67, p = 0.75; major - U = 35, p = 0.72). There was however a correlation between % operative births and minor PPH rate, but not major PPH (Spearman r = 0.32 v. Spearman r = 0.098). Conclusions Using data from trials using low risk women to generalise best practice guidelines might not be appropriate for all births, particularly complex births. Although complex births contribute disproportionately to PPH rates, this review showed they are often underrepresented in trials. Despite this, there was no difference in reported PPH rates between studies conducted in high and low risk groups. Method of birth was shown to be an important risk factor for minor PPH and may be a better predictor of PPH than antenatal risk factors. Women with operative births are often excluded from trials meaning a lack of data supporting interventions in these women. More focus on complex births is needed to ensure the evidence base is relevant to the target population.

Introduction Progress in reducing maternal and neonatal mortality, particularly in sub-Saharan Africa, is insufficient to achieve the Sustainable Developmental Goals by 2030. The first 24 hours following childbirth (immediate postnatal period), where the majority of morbidity and mortality occurs, is critical for mothers and babies. In Uganda,

Abstract Background The estimated annual global burden of miscarriage is 33 million out of 210 million pregnancies. Many women undergoing miscarriage have surgery to remove pregnancy tissues, resulting in miscarriage surgery being one of the most common operations performed in hospitals in low-income countries. Infection is a serious consequence and can result in serious illness and death. In low-income settings, the infection rate following miscarriage surgery has been reported to be high. Good quality evidence on the use of prophylactic antibiotics for surgical miscarriage management is not available. Given that miscarriage surgery is common, and infective complications are frequent and serious, prophylactic antibiotics may offer a simple and affordable intervention to improve outcomes. Methods Eligible patients will be approached once the diagnosis of miscarriage has been made according to local practice. Once informed consent has been given, participants will be randomly allocated using a secure internet facility (1:1 ratio) to a single dose of oral doxycycline (400 mg) and metronidazole (400 mg) or placebo. Allocation will be concealed to both the patient and the healthcare providers. A total of 3400 women will be randomised, 1700 in each arm. The medication will be given approximately 2 hours before surgery, which will be provided according to local practice. The primary outcome is pelvic infection 2 weeks after surgery. Women will be invited to the hospital for a clinical assessment at 2 weeks. Secondary outcomes include overall antibiotic use, individual components of the primary outcome, death, hospital admission, unplanned consultations, blood transfusion, vomiting, diarrhoea, adverse events, anaphylaxis and allergy, duration of clinical symptoms, and days before return to usual activities. An economic evaluation will be performed to determine if prophylactic antibiotics are cost-effective. Discussion This trial will assess whether a single dose of doxycycline (400 mg) and metronidazole (400 mg) taken orally 2 hours before miscarriage surgery can reduce the incidence of pelvic infection in women up to 2 weeks after miscarriage surgery. Trial registration Registered with the ISRCTN (international standard randomised controlled trial number) registry: ISRCTN 97143849. (Registered on April 17, 2013).

Abstract Background Good hand hygiene (HH) practice is crucial to reducing healthcare associated infections (HAIs). Use of alcohol-based hand rub (ABHR) at health facilities is strongly recommended but it is limited in Uganda. Data on the practice of HH and the incidence of HAIs is sparse in resource-limited settings. We conducted a quasi-experimental study to evaluate HH practices of health care providers (HCPs) utilizing locally made ABHR and the incidence of HAIs. Methods HH compliance among HCPs and the incidence of HAIs were assessed at Mbale Regional Referral Hospital, a teaching hospital in rural Uganda. Inpatients from the obstetrics/gynecology (OBGYN), pediatric and surgical departments were enrolled on their day of admission and followed up during their hospital stay. The baseline (pre-intervention) phase of 12-weeks was followed by a 12-week intervention phase where training for HH practice was provided to all HCPs present on the target wards and ABHR was supplied on the wards. Incidence of HAIs and or Systemic Inflammatory Response Syndrome (SIRS) was measured and compared between the baseline and intervention phases. Multivariate survival analysis was performed to identify associated variables with HAIs/SIRS. Results A total of 3335 patients (26.3%) were enrolled into the study from a total of 12,665 admissions on the study wards over a 24-week period. HH compliance rate significantly improved from 9.2% at baseline to 56.4% during the intervention phase (p

INTRODUCTION:Obstructed labour (OL) is an important clinical and public health problem because of the associated maternal and perinatal morbidity and mortality. Risk factors for OL and its associated obstetric squeal are usually context specific. No epidemiological study has documented the risk factors for OL in Eastern Uganda. This study was conducted to identify the risk factors for OL in Mbale Hospital. OBJECTIVE:To identify the risk factors for OL in Mbale Regional Referral and Teaching Hospital, Eastern Uganda. METHODS:We conducted a case control study with 270 cases of women with OL and 270 controls of women without OL. We consecutively enrolled eligible cases between July 2018 and February 2019. For each case, we randomly selected one eligible control admitted in the same 24-hour period. Data was collected using face-to-face interviews and a review of patient notes. Logistic regression was used to identify the risk factors for OL. RESULTS:The risk factors for OL were, being a referral from a lower health facility (AOR 6.80, 95% CI: 4.20-11.00), prime parity (AOR 2.15 95% CI: 1.26-3.66) and use of herbal medicines in active labour (AOR 2.72 95% CI: 1.49-4.96). Married participants (AOR 0.59 95% CI: 0.35-0.97) with a delivery plan (AOR 0.56 95% CI: 0.35-0.90) and educated partners (AOR 0.57 95% CI: 0.33-0.98) were less likely to have OL. In the adjusted analysis, there was no association between four or more ANC visits and OL, adjusted odds ratio [(AOR) 0.96 95% CI: 0.57-1.63)]. CONCLUSIONS:Prime parity, use of herbal medicines in labour and being a referral from a lower health facility were identified as risk factors. Being married with a delivery plan and an educated partner were protective of OL. Increased frequency of ANC attendance was not protective against obstructed labour.

Background: Being born very premature (i.e. before 32 weeks’ gestation) has an impact on survival and quality of life. Improving care at birth may improve outcomes and parents’ experiences. Objectives: To improve the quality of care and outcomes following very preterm birth. Design: We used mixed methods, including a James Lind Alliance prioritisation, a systematic review, a framework synthesis, a comparative review, qualitative studies, development of a questionnaire tool and a medical device (a neonatal resuscitation trolley), a survey of practice, a randomised trial and a protocol for a prospective meta-analysis using individual participant data. Setting: For the prioritisation, this included people affected by preterm birth and health-care practitioners in the UK relevant to preterm birth. The qualitative work on preterm birth and the development of the questionnaire involved parents of infants born at three maternity hospitals in southern England. The medical device was developed at Liverpool Women’s Hospital. The survey of practice involved UK neonatal units. The randomised trial was conducted at eight UK tertiary maternity hospitals. Participants: For prioritisation, 26 organisations and 386 individuals; for the interviews and questionnaire tool, 32 mothers and seven fathers who had a baby born before 32 weeks’ gestation for interviews evaluating the trolley, 30 people who had experienced it being used at the birth of their baby (19 mothers, 10 partners and 1 grandmother) and 20 clinicians who were present when it was being used; for the trial, 261 women expected to have a live birth before 32 weeks’ gestation, and their 276 babies. Interventions: Providing neonatal care at very preterm birth beside the mother, and with the umbilical cord intact; timing of cord clamping at very preterm birth. Main outcome measures: Research priorities for preterm birth; feasibility and acceptability of the trolley; feasibility of a randomised trial, death and intraventricular haemorrhage. Review methods: Systematic review of Cochrane reviews (umbrella review); framework synthesis of ethics aspects of consent, with conceptual framework to inform selection criteria for empirical and analytical studies. The comparative review included studies using a questionnaire to assess satisfaction with care during childbirth, and provided psychometric information. Results: Our prioritisation identified 104 research topics for preterm birth, with the top 30 ranked. An ethnographic analysis of decision-making during this process suggested ways that it might be improved. Qualitative interviews with parents about their experiences of very preterm birth identified two differences with term births: the importance of the staff appearing calm and of staff taking control. Following a comparative review, this led to the development of a questionnaire to assess parents’ views of care during very preterm birth. A systematic overview summarised evidence for delivery room neonatal care and revealed significant evidence gaps. The framework synthesis explored ethics issues in consent for trials involving sick or preterm infants, concluding that no existing process is ideal and identifying three important gaps. This led to the development of a two-stage consent pathway (oral assent followed by written consent), subsequently evaluated in our randomised trial. Our survey of practice for care at the time of birth showed variation in approaches to cord clamping, and that no hospitals were providing neonatal care with the cord intact. We showed that neonatal care could be provided beside the mother using either the mobile neonatal resuscitation trolley we developed or existing equipment. Qualitative interviews suggested that neonatal care beside the mother is valued by parents and acceptable to clinicians. Our pilot randomised trial compared cord clamping after 2 minutes and initial neonatal care, if needed, with the cord intact, with clamping within 20 seconds and initial neonatal care after clamping. This study demonstrated feasibility of a large UK randomised trial. Of 135 infants allocated to cord clamping ≥ 2 minutes, 7 (5.2%) died and, of 135 allocated to cord clamping ≤ 20 seconds, 15 (11.1%) died (risk difference –5.9%, 95% confidence interval –12.4% to 0.6%). Of live births, 43 out of 134 (32%) allocated to cord clamping ≥ 2 minutes had intraventricular haemorrhage compared with 47 out of 132 (36%) allocated to cord clamping ≤ 20 seconds (risk difference –3.5%, 95% CI –14.9% to 7.8%). Limitations: Small sample for the qualitative interviews about preterm birth, single-centre evaluation of neonatal care beside the mother, and a pilot trial. Conclusions: Our programme of research has improved understanding of parent experiences of very preterm birth, and informed clinical guidelines and the research agenda. Our two-stage consent pathway is recommended for intrapartum clinical research trials. Our pilot trial will contribute to the individual participant data meta-analysis, results of which will guide design of future trials. Future work: Research in preterm birth should take account of the top priorities. Further evaluation of neonatal care beside the mother is merited, and future trial of alternative policies for management of cord clamping should take account of the meta-analysis. Study registration: This study is registered as PROSPERO CRD42012003038 and CRD42013004405. In addition, Current Controlled Trials ISRCTN21456601. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 8. See the NIHR Journals Library website for further project information.

Background: Obesity may affect both biochemical thyroid function tests; and thyroid morphology, as assessed using ultrasound scans (US). The aim of the present pilot study was to explore whether weight loss achieved by bariatric surgery alters thyroid US morphology including gray-scale measurements; and/or function in euthyroid adults with severe obesity.Methods: Euthyroid adults (>18 years) with body mass index (BMI) ≥40 kg/m2 and negative thyroid peroxidase antibodies were assessed at baseline (pre-surgery) and after achieving at least 5% weight loss of their baseline body weight following bariatric surgery. Anthropometric assessments, biochemical/hormonal measurements (TSH, free-T4, free-T3, reverse-T3, and leptin) and thyroid US with gray-scale histogram analysis were performed at the baseline and post-surgery follow-up.Results: Ten Caucasian, euthyroid patients (women/men: 8/2; age: 48.6 ± 3.1 years; BMI: 51.4 ± 1.8 kg/m2) successfully completed this study with significantly decreased body weight (>5% weight loss), waist circumference and serum leptin levels post-surgery (mean post-surgery follow-up duration: 16.5 ± 2.5 months). In parallel to the observed bariatric-induced weight loss, thyroid US echogenicity increased by 25% (p = 0.03), without significant changes in thyroid volume. No significant changes in thyroid function tests were detected. No significant correlations were observed between the increase in thyroid echogenicity and the decreases in anthropometric parameters and circulating leptin.Conclusion: Our results indicate that in euthyroid adults with severe obesity, marked weight loss achieved by bariatric surgery is associated with a parallel significant increase in the thyroid US echogenicity, suggesting that morphological changes of the thyroid in obesity are reversible with weight loss.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03048708

Septin proteins bind guanine nucleotides and form rod-shaped hetero-oligomers. Cells choose from a variety of available septins to assemble distinct hetero-oligomers, but the underlying mechanism was unknown. Using a new in vivo assay, we find that a stepwise assembly pathway produces the two species of budding yeast septin hetero-octamers: Cdc11/Shs1–Cdc12–Cdc3–Cdc10–Cdc10–Cdc3–Cdc12–Cdc11/Shs1. Rapid GTP hydrolysis by monomeric Cdc10 drives assembly of the core Cdc10 homodimer. The extended Cdc3 N terminus autoinhibits Cdc3 association with Cdc10 homodimers until prior Cdc3–Cdc12 interaction. Slow hydrolysis by monomeric Cdc12 and specific affinity of Cdc11 for transient Cdc12•GTP drive assembly of distinct trimers, Cdc11–Cdc12–Cdc3 or Shs1–Cdc12–Cdc3. Decreasing the cytosolic GTP:GDP ratio increases the incorporation of Shs1 vs Cdc11, which alters the curvature of filamentous septin rings. Our findings explain how GTP hydrolysis controls septin assembly, and uncover mechanisms by which cells construct defined septin complexes.

Background: Maternal obesity is associated with high birthweight, obesity and premature mortality in adult offspring, probably as a result of maternal hyperglycaemia and insulin resistance. We present the results of a trial designed to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high-birthweight babies. Objective: To determine the efficacy of metformin (up to 2500 mg daily) given to obese pregnant women in reducing the gestational age-, parity- and sex-adjusted birthweight centile of the baby. Design: Double-blind, placebo-controlled, randomised controlled trial with embedded substudies. Setting: Fifteen NHS hospitals in the UK. Participants: Pregnant women aged ≥ 16 years with a singleton fetus and a body mass index of ≥ 30 kg/m2. Intervention: Metformin tablets (or placebo) administered between 12 and 16 weeks’ gestation until delivery of the baby. Main outcome measures: The primary outcome measure was z-score corresponding to the gestational age-, parity- and sex-adjusted birthweight centile of live-born babies delivered at ≥ 24 weeks’ gestation. The main secondary outcome was maternal insulin resistance at 36 weeks’ gestation. Embedded substudies were included to assess the effect of metformin on insulin sensitivity using the hyperinsulinaemic–euglycaemic clamp; endothelial function; maternal and fetal fat distribution using magnetic resonance imaging; placental expression of 11β-hydroxysteroid dehydrogenase types 1 and 2 and glucocorticoid receptor; and myometrial contractility and glycogen storage. Results: We randomised 449 women to either placebo (n = 223) or metformin (n = 226), of whom 434 were included in the final intention-to-treat analysis. Mean birthweight at delivery was 3463 g [standard deviation (SD) 660 g] in the placebo group and 3462 g (SD 548 g) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant [adjusted mean difference in z-score –0.029, 95% confidence interval (CI) –0.217 to 0.158; p = 0.7597]. There was no evidence of a reduction in the main secondary outcome of homeostatic model assessment – insulin resistance (HOMA-IR) at 36 weeks’ gestation (mean HOMA-IR 5.98 and 6.30 molar units in the placebo and metformin groups, respectively; adjusted mean ratio 0.974, 95% CI 0.865 to 1.097). Metformin had no effect on the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth or neonatal death. Subjects taking metformin demonstrated increased insulin sensitivity [glucose disposal per unit plasma insulin difference between means during high-dose insulin 0.02 mg/kg, 95% CI 0.001 to 0.03 mg/kg (fat-free mass)/minute/µIU/l; p = 0.04] compared with those taking placebo and enhanced endogenous glucose production [difference between means 0.54 mg/kg, 95% CI 0.08 to 1.00 mg/kg (fat-free mass)/minute; p = 0.02]. There were no differences in endothelial function, maternal or fetal body fat distribution, placental expression of 11β-hydroxysteroid dehydrogenase types 1 and 2 and glucocorticoid receptor, or myometrial contractility and glycogen storage. Conclusions: Metformin has no clinically significant effect on birthweight centile in obese pregnant women. Follow-up studies of the children born to participants in the trial are required to determine whether or not there are any longer-term benefits or harms of maternal metformin for offspring weight, fat mass or metabolism. Trial registration: Current Controlled Trials ISRCTN51279843. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.