Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clients.

It is not understood how Hsp104, a hexameric AAA+ ATPase from yeast, disaggregates diverse structures, including stress-induced aggregates, prions, and α-synuclein conformers connected to Parkinson disease. Here, we establish that Hsp104 hexamers adapt different mechanisms of intersubunit collaboration to disaggregate stress-induced aggregates versus amyloid. To resolve disordered aggregates, Hsp104 subunits collaborate noncooperatively via probabilistic substrate binding and ATP hydrolysis. To disaggregate amyloid, several subunits cooperatively engage substrate and hydrolyze ATP. Importantly, Hsp104 variants with impaired intersubunit communication dissolve disordered aggregates, but not amyloid. Unexpectedly, prokaryotic ClpB subunits collaborate differently than Hsp104 and couple probabilistic substrate binding to cooperative ATP hydrolysis, which enhances disordered aggregate dissolution but sensitizes ClpB to inhibition and diminishes amyloid disaggregation. Finally, we establish that Hsp104 hexamers deploy more subunits to disaggregate Sup35 prion strains with more stable "cross-ß" cores. Thus, operational plasticity enables Hsp104 to robustly dissolve amyloid and nonamyloid clients, which impose distinct mechanical demands.

YAP activation inhibits inflammatory signalling and cartilage breakdown associated with reduced primary cilia expression.

OBJECTIVE: To clarify the role of YAP in modulating cartilage inflammation and degradation and the involvement of primary cilia and associated intraflagellar transport (IFT). METHODS: Isolated primary chondrocytes were cultured on substrates of different stiffness (6-1000 kPa) or treated with YAP agonist lysophosphatidic acid (LPA) or YAP antagonist verteporfin (VP), or genetically modified by YAP siRNA, all ± IL1ß. Nitric oxide (NO) and prostaglandin E2 (PGE2) release were measured to monitor IL1ß response. YAP activity was quantified by YAP nuclear/cytoplasmic ratio and percentage of YAP-positive cells. Mechanical properties of cartilage explants were tested to confirm cartilage degradation. The involvement of primary cilia and IFT was analysed using IFT88 siRNA and ORPK cells with hypomorphic mutation of IFT88. RESULTS: Treatment with LPA, or increasing polydimethylsiloxane (PDMS) substrate stiffness, activated YAP nuclear expression and inhibited IL1ß-induced release of NO and PGE2, in isolated chondrocytes. Treatment with LPA also inhibited IL1ß-mediated inflammatory signalling in cartilage explants and prevented matrix degradation and the loss of cartilage biomechanics. YAP activation reduced expression of primary cilia, knockdown of YAP in the absence of functional cilia/IFT failed to induce an inflammatory response. CONCLUSIONS: We demonstrate that both pharmaceutical and mechanical activation of YAP blocks pro-inflammatory signalling induced by IL1ß and prevents cartilage breakdown and the loss of biomechanical functionality. This is associated with reduced expression of primary cilia revealing a potential anti-inflammatory mechanism with novel therapeutic targets for treatment of osteoarthritis (OA).

Incidence and outcomes of uterine rupture in women with unscarred, preterm or prelabour uteri: data from the international network of obstetric survey systems.

OBJECTIVE: Analysis of atypical cases of uterine rupture, namely, uterine rupture occurring in unscarred, preterm or prelabour uteri. DESIGN: Descriptive multi-country population-based study. SETTING: Ten high-income countries within the International Network of Obstetric Survey Systems. POPULATION: Women with unscarred, preterm or prelabour ruptured uteri. METHODS: We merged prospectively collected individual patient data in ten population-based studies of women with complete uterine rupture. In this analysis, we focused on women with uterine rupture of unscarred, preterm or prelabour ruptured uteri. MAIN OUTCOME MEASURES: Incidence, women's characteristics, presentation and maternal and perinatal outcome. RESULTS: We identified 357 atypical uterine ruptures in 3 064 923 women giving birth. Estimated incidence was 0.2 per 10 000 women (95% CI 0.2-0.3) in the unscarred uteri, 0.5 (95% CI 0.5-0.6) in the preterm uteri, 0.7 (95% CI 0.6-0.8) in the prelabour uteri, and 0.5 (95% CI 0.4-0.5) in the group with no previous caesarean. Atypical uterine rupture resulted in peripartum hysterectomy in 66 women (18.5%, 95% CI 14.3-23.5%), three maternal deaths (0.84%, 95% CI 0.17-2.5%) and perinatal death in 62 infants (19.7%, 95% CI 15.1-25.3%). CONCLUSIONS: Uterine rupture in preterm, prelabour or unscarred uteri are extremely uncommon but were associated with severe maternal and perinatal outcome. We found a mix of risk factors in unscarred uteri, most preterm uterine ruptures occurred in caesarean-scarred uteri and most prelabour uterine ruptures in 'otherwise' scarred uteri. This study may increase awareness among clinicians and raise suspicion of the possibility of uterine rupture under these less expected conditions.

A national cohort study to investigate the association between ethnicity and the provision of care in obstetric anaesthesia in England between 2011 and 2021.

There is evidence that ethnic inequalities exist in maternity care in the UK, but those specifically in relation to UK obstetric anaesthetic care have not been investigated before. Using routine national maternity data for England (Hospital Episode Statistics Admitted Patient Care) collected between March 2011 and February 2021, we investigated ethnic differences in obstetric anaesthetic care. Anaesthetic care was identified using OPCS classification of interventions and procedures codes. Ethnic groups were coded according to the hospital episode statistics classifications. Multivariable negative binominal regression was used to model the relationship between ethnicity and obstetric anaesthesia (general and neuraxial anaesthesia) by calculating adjusted incidence ratios for the following: differences in maternal age; geographical residence; deprivation; admission year; number of previous deliveries; and comorbidities. Women giving birth vaginally and by caesarean section were considered separately. For women undergoing elective caesarean births, after adjustment for available confounders, general anaesthesia was 58% more common in Caribbean (black or black British) women (adjusted incidence ratio [95%CI] 1.58 [1.26-1.97]) and 35% more common in African (black or black British) women (1.35 [1.19-1.52]). For women who had emergency caesarean births, general anaesthesia was 10% more common in Caribbean (black or black British) women (1.10 [1.00-1.21]) than British (white) women. For women giving birth vaginally (excluding assisted vaginal births), Bangladeshi (Asian or Asian British), Pakistani (Asian or Asian British) and Caribbean (black or black British) women were, respectively, 24% (0.76 [0.74-0.78]), 15% (0.85 [0.84-0.87]) and 8% (0.92 [0.89-0.94]) less likely than British (white) women to receive neuraxial anaesthesia. This observational study cannot determine the causes for these disparities, which may include unaccounted confounders. Our findings merit further research to investigate potentially remediable factors such as inequality of access to appropriate obstetric anaesthetic care.

Defining vulnerability subgroups among pregnant women using pre-pregnancy information: a latent class analysis.

BACKGROUND: Early detection of vulnerability during or before pregnancy can contribute to optimizing the first 1000 days, a crucial period for children's development and health. We aimed to identify classes of vulnerability among pregnant women in the Netherlands using pre-pregnancy data on a wide range of social risk and protective factors, and validate these classes against the risk of adverse outcomes. METHODS: We conducted a latent class analysis based on 42 variables derived from nationwide observational data sources and self-reported data. Variables included individual, socioeconomic, lifestyle, psychosocial and household characteristics, self-reported health, healthcare utilization, life-events and living conditions. We compared classes in relation to adverse outcomes using logistic regression analyses. RESULTS: In the study population of 4172 women, we identified five latent classes. The largest 'healthy and socioeconomically stable'-class [n = 2040 (48.9%)] mostly shared protective factors, such as paid work and positively perceived health. The classes 'high care utilization' [n = 485 (11.6%)], 'socioeconomic vulnerability' [n = 395 (9.5%)] and 'psychosocial vulnerability' [n = 1005 (24.0%)] were characterized by risk factors limited to one specific domain and protective factors in others. Women classified into the 'multidimensional vulnerability'-class [n = 250 (6.0%)] shared multiple risk factors in different domains (psychosocial, medical and socioeconomic risk factors). Multidimensional vulnerability was associated with adverse outcomes, such as premature birth and caesarean section. CONCLUSIONS: Co-existence of multiple risk factors in various domains is associated with adverse outcomes for mother and child. Early detection of vulnerability and strategies to improve parental health and well-being might benefit from focussing on different domains and combining medical and social care and support.

Healthy Foods in Convenience Stores: Benefits, Barriers, and Best Practices.

Accessing healthy food is a challenge for many. Healthy corner store initiatives have proven successful at promoting healthy food access nationwide. Recent data suggest that 11.8% of Clark County residents and 17.1% of Henderson, Nevada, residents experienced food insecurity. It is crucial to assess the current perceptions and practices of the community before pursuing policy change to ensure that pilot programs reflect its members' needs. This study aimed to identify which healthy foods consumers would like to see offered in convenience stores, assess purchasing behaviors, and explore barriers preventing store owners from carrying healthy foods. In doing so, this study aimed to ensure that the needs of owners and consumers are reflected in local policy changes. Project staff collected data through two approaches: (a) convenience store owner interviews (n = 2; who represented eight stores total) and (b) consumer intercept surveys (n = 88) within low-income census tracts of Henderson, Nevada. The cost of healthy foods-for storeowners and consumers-was a major factor when selecting items to stock. Storeowners also described key contextual barriers such as minimum purchasing requirements, city regulations limiting promotions, and healthy, fresh food not being in high enough demand for the many transient customers passing through. Survey respondents' most commonly reported barrier to accessing healthy food was their lack of availability in convenience stores, suggesting it would be beneficial if stores offered healthier options to increase access. The results of this study will inform the community's next steps to increase access to healthy foods, including implementing a pilot healthy corner store project and a City-sponsored marketing campaign. Our methods and lessons learned may be useful for other municipalities considering health corner and convenience store initiatives.

Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1ß mediated articular cartilage matrix destruction.

OBJECTIVE: Cartilage health is maintained in response to a range of mechanical stimuli including compressive, shear and tensile strains and associated alterations in osmolality. The osmotic-sensitive ion channel Transient Receptor Potential Vanilloid 4 (TRPV4) is required for mechanotransduction. Mechanical stimuli inhibit interleukin-1ß (IL-1ß) mediated inflammatory signalling, however the mechanism is unclear. This study aims to clarify the role of TRPV4 in this response. DESIGN: TRPV4 activity was modulated glycogen synthase kinase (GSK205 antagonist or GSK1016790 A (GSK101) agonist) in articular chondrocytes and cartilage explants in the presence or absence of IL-1ß, mechanical (10% cyclic tensile strain (CTS), 0.33 Hz, 24hrs) or osmotic loading (200mOsm, 24hrs). Nitric oxide (NO), prostaglandin E2 (PGE2) and sulphated glycosaminoglycan (sGAG) release and cartilage biomechanics were analysed. Alterations in post-translational tubulin modifications and primary cilia length regulation were examined. RESULTS: In isolated chondrocytes, mechanical loading inhibited IL-1ß mediated NO and PGE2 release. This response was inhibited by GSK205. Similarly, osmotic loading was anti-inflammatory in cells and explants, this response was abrogated by TRPV4 inhibition. In explants, GSK101 inhibited IL-1ß mediated NO release and prevented cartilage degradation and loss of mechanical properties. Upon activation, TRPV4 cilia localisation was increased resulting in histone deacetylase 6 (HDAC6)-dependent modulation of soluble tubulin and altered cilia length regulation. CONCLUSION: Mechanical, osmotic or pharmaceutical activation of TRPV4 regulates HDAC6-dependent modulation of ciliary tubulin and is anti-inflammatory. This study reveals for the first time, the potential of TRPV4 manipulation as a novel therapeutic mechanism to supress pro-inflammatory signalling and cartilage degradation.

The identification of key indicators to drive quality improvement in obstetric anaesthesia: results of the Obstetric Anaesthetists' Association/National Perinatal Epidemiology Unit collaborative Delphi project.

A three-stage Delphi survey process was undertaken to identify the quality indicators considered the most relevant to obstetric anaesthesia. The initial quality indicators assessed were derived from national peer-reviewed publications and were divided into service provision, service quality and clinical outcomes. A range of stakeholders were invited to participate and divided into three panels: obstetric anaesthetists; other maternity care health professionals; and women who had used maternity services. In total, 133 stakeholders registered to participate with 80% completing all three phases of the survey process. Participants ranked indicators for their relative importance using the grading of recommendations assessment, development and evaluation scale. From an initial list of 31 quality indicators, 11 indicators were rated as extremely important by > 90% of participants in at least two panels. These 11 indicators were presented to stakeholders; they were asked to vote for the five indicators they considered most relevant and useful for assessing and benchmarking the quality of obstetric anaesthesia provided. The indicators chosen were: the percentage of women who had an epidural/combined spinal-epidural for labour analgesia with accidental dural puncture; the presence of guidelines for the referral of patients to an anaesthetist for antenatal review; whether there are dedicated elective caesarean section lists; the availability of point-of-care testing for estimation of haemoglobin concentration; and the percentage of epidurals for labour analgesia that provided adequate pain relief within 45 min of the start of epidural insertion. These indicators may be used for quality improvement and national benchmarking to support the implementation of quality standards in obstetric anaesthesia.

Anaphylaxis in pregnancy: a population-based multinational European study.

Anaphylaxis in pregnancy is a rare but severe complication for both mother and infant. Population-based data on anaphylaxis in pregnancy are lacking from mainland European countries. This multinational study presents the incidence, causative agents, management and maternal and infant outcomes of anaphylaxis in pregnancy. This descriptive multinational study used a combination of retrospective (Finnish medical registries) and prospective population-based studies (UK, France, Belgium and the Netherlands) to identify cases of anaphylaxis. Sixty-five cases were identified among 4,446,120 maternities (1.5 per 100,000 maternities; 95%CI 1.1-1.9). The incidence did not vary between countries. Approximately three-quarters of reactions occurred at the time of delivery. The most common causes were antibiotics in 27 women (43%), and anaesthetic agents in 11 women (17%; including neuromuscular blocking drugs, 7), which varied between countries. Anaphylaxis had very poor outcomes for one in seven mothers and one in seven babies; the maternal case fatality rate was 3.2% (95%CI 0.4-11.0) and the neonatal encephalopathy rate was 14.3% (95%CI 4.8-30.3). Across Europe, anaphylaxis related to pregnancy is rare despite having a multitude of causative agents and different antibiotic prophylaxis protocols.

Mechanical loading inhibits cartilage inflammatory signalling via an HDAC6 and IFT-dependent mechanism regulating primary cilia elongation.

OBJECTIVE: Physiological mechanical loading reduces inflammatory signalling in numerous cell types including articular chondrocytes however the mechanism responsible remains unclear. This study investigates the role of chondrocyte primary cilia and associated intraflagellar transport (IFT) in the mechanical regulation of interleukin-1ß (IL-1ß) signalling. DESIGN: Isolated chondrocytes and cartilage explants were subjected to cyclic mechanical loading in the presence and absence of the cytokine IL-1ß. Nitric oxide (NO) and prostaglandin E2 (PGE2) release were used to monitor IL-1ß signalling whilst Sulphated glycosaminoglycan (sGAG) release provided measurement of cartilage degradation. Measurements were made of HDAC6 activity and tubulin polymerisation and acetylation. Effects on primary cilia were monitored by confocal and super resolution microscopy. Involvement of IFT was analysed using ORPK cells with hypomorphic mutation of IFT88. RESULTS: Mechanical loading suppressed NO and PGE2 release and prevented cartilage degradation. Loading activated HDAC6 and disrupted tubulin acetylation and cilia elongation induced by IL-1ß. HDAC6 inhibition with tubacin blocked the anti-inflammatory effects of loading and restored tubulin acetylation and cilia elongation. Hypomorphic mutation of IFT88 reduced IL-1ß signalling and abolished the anti-inflammatory effects of loading indicating the mechanism is IFT-dependent. Loading reduced the pool of non-polymerised tubulin which was replicated by taxol which also mimicked the anti-inflammatory effects of mechanical loading and prevented cilia elongation. CONCLUSIONS: This study reveals that mechanical loading suppresses inflammatory signalling, partially dependent on IFT, by activation of HDAC6 and post transcriptional modulation of tubulin.

Nanoscale spatial limitations of large-area substrate conformal imprint lithography.

We demonstrate a soft-imprint nanofabrication technique offering nanometer resolution over an area as large as a 150 mm diameter wafer. It makes use of a composite imprint stamp composed of a quaternary siloxane-modified poly-di-methyl-siloxane patterned rubber layer with a relatively high Young's modulus that is laminated on a thin glass support. The in-plane stiffness of the stamp avoids pattern deformation over large areas, while out-of-plane flexibility allows conformal contact to be made over the entire substrate area. The stamp is used in conjunction with a novel tetra-methyl-ortho-siloxane/methyl-tri-methoxy-siloxane sol-gel imprint resist material developed to replicate nanoscale features in rigid silica at room temperature. We demonstrate better than 10 nm resolution in imprinted line gratings and individual pillars with aspect ratio as high as 5:1. Gaps as small as 6 nm can be reproduced. The patterns can be used as an etch mask to pattern 150 mm diameter silicon and quartz substrates while maintaining sub-10 nm resolution.

Surveillance of congenital Zika syndrome in England and Wales: methods and results of laboratory, obstetric and paediatric surveillance.

The spread of the Zika virus (ZIKV) in the Americas led to large outbreaks across the region and most of the Southern hemisphere. Of greatest concern were complications following acute infection during pregnancy. At the beginning of the outbreak, the risk to unborn babies and their clinical presentation was unclear. This report describes the methods and results of the UK surveillance response to assess the risk of ZIKV to children born to returning travellers. Established surveillance systems operating within the UK - the paediatric and obstetric surveillance units for rare diseases, and national laboratory monitoring - enabled rapid assessment of this emerging public health threat. A combined total of 11 women experiencing adverse pregnancy outcomes after possible ZIKV exposure were reported by the three surveillance systems; five miscarriages, two intrauterine deaths and four children with clinical presentations potentially associated with ZIKV infection. Sixteen women were diagnosed with ZIKV during pregnancy in the UK. Amongst the offspring of these women, there was unequivocal laboratory evidence of infection in only one child. In the UK, the number and risk of congenital ZIKV infection for travellers returning from ZIKV-affected countries is very small.

The DiPEP study: an observational study of the diagnostic accuracy of clinical assessment, D-dimer and chest x-ray for suspected pulmonary embolism in pregnancy and postpartum.

OBJECTIVE: To identify clinical features associated with pulmonary embolism (PE) diagnosis and determine the accuracy of decision rules and D-dimer for diagnosing suspected PE in pregnant/postpartum women DESIGN: Observational cohort study augmented with additional cases. SETTING: Emergency departments and maternity units at eleven prospectively recruiting sites and maternity units in the United Kingdom Obstetric Surveillance System (UKOSS) POPULATION: 324 pregnant/postpartum women with suspected PE and 198 pregnant/postpartum women with diagnosed PE METHODS: We recorded clinical features, elements of clinical decision rules, D-dimer measurements, imaging results, treatments and adverse outcomes up to 30 days MAIN OUTCOME MEASURES: Women were classified as having PE on the basis of imaging, treatment and adverse outcomes by assessors blind to clinical features and D-dimer. Primary analysis was limited to women with conclusive imaging to avoid work-up bias. Secondary analyses included women with clinically diagnosed or ruled out PE. RESULTS: The only clinical features associated with PE on multivariate analysis were age (odds ratio 1.06; 95% confidence interval 1.01-1.11), previous thrombosis (3.07; 1.05-8.99), family history of thrombosis (0.35; 0.14-0.90), temperature (2.22; 1.26-3.91), systolic blood pressure (0.96; 0.93-0.99), oxygen saturation (0.87; 0.78-0.97) and PE-related chest x-ray abnormality (13.4; 1.39-130.2). Clinical decision rules had areas under the receiver-operator characteristic curve ranging from 0.577 to 0.732 and no clinically useful threshold for decision-making. Sensitivities and specificities of D-dimer were 88.4% and 8.8% using a standard threshold and 69.8% and 32.8% using a pregnancy-specific threshold. CONCLUSIONS: Clinical decision rules and D-dimer should not be used to select pregnant or postpartum women with suspected PE for further investigation. Clinical features and chest x-ray appearances may have counter-intuitive associations with PE in this context. TWEETABLE ABSTRACT: Clinical decision rules and D-dimer are not helpful for diagnosing pregnant/postpartum women with suspected PE.

Defining definitions: a Delphi study to develop a core outcome set for conditions of severe maternal morbidity.

OBJECTIVE: Develop a core outcome set of international consensus definitions for severe maternal morbidities. DESIGN: Electronic Delphi study. SETTING: International. POPULATION: Eight expert panels. METHODS: All 13 high-income countries represented in the International Network of Obstetric Surveillance Systems (INOSS) nominated five experts per condition of morbidity, who submitted possible definitions. From these suggestions, a steering committee distilled critical components: eclampsia: 23, amniotic fluid embolism: 15, pregnancy-related hysterectomy: 11, severe primary postpartum haemorrhage: 19, uterine rupture: 20, abnormally invasive placentation: 12, spontaneous haemoperitoneum in pregnancy: 16, and cardiac arrest in pregnancy: 10. These components were assessed by the expert panel using a 5-point Likert scale, following which a framework for an encompassing definition was constructed. Possible definitions were evaluated in rounds until a rate of agreement of more than 70% was reached. Expert commentaries were used in each round to improve definitions. MAIN OUTCOME MEASURES: Definitions with a rate of agreement of more than 70%. RESULTS: The invitation to participate in one or more of eight Delphi processes was accepted by 103 experts from 13 high-income countries. Consensus definitions were developed for all of the conditions. CONCLUSION: Consensus definitions for eight morbidity conditions were successfully developed using the Delphi process. These should be used in national registrations and international studies, and should be taken up by the Core Outcomes in Women's and Newborn Health initiative. TWEETABLE ABSTRACT: Consensus definitions for eight morbidity conditions were successfully developed using the Delphi process.

The International Network of Obstetric Survey Systems study of uterine rupture: a descriptive multi-country population-based study.

OBJECTIVE: International comparison of complete uterine rupture. DESIGN: Descriptive multi-country population-based study. SETTING: International. POPULATION: International Network of Obstetric Survey Systems (INOSS). METHODS: We merged individual data, collected prospectively in nine population-based studies, of women with complete uterine rupture, defined as complete disruption of the uterine muscle and the uterine serosa, regardless of symptoms and rupture of fetal membranes. MAIN OUTCOME MEASURES: Prevalence of complete uterine rupture, regional variation and correlation with rates of caesarean section (CS) and trial of labour after CS (TOLAC). Severe maternal and perinatal morbidity and mortality. RESULTS: We identified 864 complete uterine ruptures in 2 625 017 deliveries. Overall prevalence was 3.3 (95% CI 3.1-3.5) per 10 000 deliveries, 22 (95% CI 21-24) in women with and 0.6 (95% CI 0.5-0.7) in women without previous CS. Prevalence in women with previous CS was negatively correlated with previous CS rate (ρ = -0.917) and positively correlated with TOLAC rate of the background population (ρ = 0.600). Uterine rupture resulted in peripartum hysterectomy in 87 of 864 women (10%, 95% CI 8-12%) and in a perinatal death in 116 of 874 infants (13.3%, 95% CI 11.2-15.7) whose mother had uterine rupture. Overall rate of neonatal asphyxia was 28% in neonates who survived. CONCLUSIONS: Higher prevalence of complete uterine ruptures per TOLAC was observed in countries with low previous CS and high TOLAC rates. Rates of hysterectomy and perinatal death are about 10% following complete uterine rupture, but in women undergoing TOLAC the rates are extremely low (only 2.2 and 3.2 per 10 000 TOLACs, respectively.) TWEETABLE ABSTRACT: Prevalence of complete uterine rupture is higher in countries with low previous CS and high TOLAC rates.

Identifying avoidable switchboard delays in England's NHS hospitals: phase one of the national SWITCH project.

BACKGROUND: Inter-hospital communication frequently requires mediation via a switchboard. Identifying and eliminating switchboard inefficiencies may improve patient care. METHODS: All 175 acute hospital switchboards in England were contacted six times. Call contents and duration were recorded. No clinician calls or bleeps were connected. RESULTS: The mean delay before contacting a switchboard operative was 55±46 seconds. 115 hospitals (66%) used automated switchboards; 34 of these (30%) had infection control messages. Robot operators introduced an additional 40 second delay versus humans (mean 70.3±28 versus 29.8±23 seconds, p<0.0001). Multivariate analysis identified robot operators (HR 5.1, p<0.0001) and infection control messages (HR 2.9, p=0.003) as predictors of delays over 60 seconds. CONCLUSIONS: There are significant avoidable delays in contacting switchboard operatives across England. Quality improvement is underway.

Cobalt ions stimulate a fibrotic response through matrix remodelling, fibroblast contraction and release of pro-fibrotic signals from macrophages.

Many studies report the adverse responses to metal-on-metal (MoM) hip prostheses, with tissues surrounding failed MoM hip prostheses revealing abundant tissue necrosis and fibrosis. These local effects appear to be initiated by metal ions released from the prosthesis causing the secretion of inflammatory mediators. However, little is known about the effect of the metal ions on tissue remodelling and pseudotumor formation, which are also associated with the failure of MoM hip prostheses. The peri-prosthetic soft tissue masses can lead to pain, swelling, limited range of joint movement and extensive tissue lesion. To elucidate this cellular response, a multidisciplinary approach using both two- and three-dimensional (2D and 3D) in vitro culture systems was employed to study the effects of Co2+ and Cr3+ on human fibroblast activation and mechanobiology. Co2+ induced a fibrotic response, characterised by cytoskeletal remodelling and enhanced collagen matrix contraction. This was associated with increased cell stiffness and contractile forces as measured by atomic force microscopy and traction force microscopy, respectively. These effects were triggered by the generation of reactive oxygen species (ROS). Moreover, this fibrotic response was enhanced in the presence of macrophages, which increased the prevalence of a-smooth muscle actin (a-SMA)-positive fibroblasts and collagen synthesis. Cr3+ did not show any significant effect on fibroblast activation. Co2+ promoted matrix remodelling by fibroblasts that was further enhanced by macrophage signalling. Use of alternative implant materials or manipulation of this fibrotic response could provide an opportunity for enhancing the success of prostheses utilising CoCr alloys.

Severe primary autoimmune thrombocytopenia in pregnancy: a national cohort study.

OBJECTIVE: To quantify the incidence of severe autoimmune thrombocytopenia (ITP) in pregnancy in the UK, determine current treatment strategies, and establish maternal and neonatal morbidity and mortality associated with severe ITP in pregnancy. DESIGN: A prospective national cohort study. SETTING: UK. POPULATION: Women with severe ITP, defined as platelets <50 × 109 /L in pregnancy or antenatal treatment of isolated low platelets. METHODS: Data collected via the UK Obstetric Surveillance System (UKOSS) between 1 June 2013 and 31 January 2015 from all UK consultant-led obstetric units. MAIN OUTCOME MEASURE: Incidence of severe ITP in pregnancy. RESULTS: The estimated incidence of severe ITP in pregnancy is 0.83 per 10 000 maternities (95% CI 0.68-1.00). A total of 22 pregnant women (21%) did not receive any antenatal therapy, and 85 pregnant women (79%) received therapy. There was no difference between asymptomatic treated and untreated cohorts in severity of disease or outcome. Postpartum haemorrhage (51%) and severe postpartum haemorrhage (21%) was reported more frequently than the rate reported in the general pregnant population (5-10%). No neonates required treatment for thrombocytopenia and there were no cases of neonatal intracranial bleeding. CONCLUSIONS: Current UK management of severe ITP in pregnancy results in an exceptionally low morbidity and mortality for the neonate. Mothers with ITP remain at increased risk of severe postpartum haemorrhage, and should be delivered at units that have the capacity to manage severe PPH effectively. Whilst balancing the risks for pregnancy from prophylactic antenatal treatment in asymptomatic women against observed low disease morbidity, we may be over treating asymptomatic patients. TWEETABLE ABSTRACT: UKOSS study of severe ITP in pregnancy shows exceptionally low neonatal morbidity with current UK management.

Developing a set of consensus indicators to support maternity service quality improvement: using Core Outcome Set methodology including a Delphi process.

OBJECTIVE: To develop a core metric set to monitor the quality of maternity care. DESIGN: Delphi process followed by a face-to-face consensus meeting. SETTING: English maternity units. POPULATION: Three representative expert panels: service designers, providers and users. MAIN OUTCOME MEASURES: Maternity care metrics judged important by participants. METHODS: Participants were asked to complete a two-phase Delphi process, scoring metrics from existing local maternity dashboards. A consensus meeting discussed the results and re-scored the metrics. RESULTS: In all, 125 distinct metrics across six domains were identified from existing dashboards. Following the consensus meeting, 14 metrics met the inclusion criteria for the final core set: smoking rate at booking; rate of birth without intervention; caesarean section delivery rate in Robson group 1 women; caesarean section delivery rate in Robson group 2 women; caesarean section delivery rate in Robson group 5 women; third- and fourth-degree tear rate among women delivering vaginally; rate of postpartum haemorrhage of ≥1500 ml; rate of successful vaginal birth after a single previous caesarean section; smoking rate at delivery; proportion of babies born at term with an Apgar score <7 at 5 minutes; proportion of babies born at term admitted to the neonatal intensive care unit; proportion of babies readmitted to hospital at <30 days of age; breastfeeding initiation rate; and breastfeeding rate at 6-8 weeks. CONCLUSIONS: Core outcome set methodology can be used to incorporate the views of key stakeholders in developing a core metric set to monitor the quality of care in maternity units, thus enabling improvement. TWEETABLE ABSTRACT: Achieving consensus on core metrics for monitoring the quality of maternity care.

Hormone-secreting adrenal tumours cause severe hypertension and high rates of poor pregnancy outcome; a UK Obstetric Surveillance System study with case control comparisons.

OBJECTIVE: To examine the management and outcomes of adrenal tumours in pregnancy. DESIGN: A national observational, cohort study over 4 years using the UK Obstetric Surveillance System (UKOSS). SETTING: Consultant-led obstetric units. PATIENTS: Women with phaeochromocytoma, primary aldosteronism or Cushing's syndrome diagnosed before or during pregnancy. METHODS: Clinical features of UKOSS cases were compared with those of women with adrenal tumours reported from 1985-2015. Nested case-control comparisons involving the UKOSS cases as well as those identified in the literature were performed for pregnancy outcome data using UKOSS controls with uncomplicated singleton (n = 2250) pregnancy and data from the Office of National Statistics (ONS). MAIN OUTCOME MEASURES: Incidence, management and frequency of adverse maternal and offspring outcomes of adrenal tumours in pregnancy. RESULTS: Fifteen pregnant women met the inclusion criteria: ten phaeochromocytoma, three primary aldosteronism and two Cushing's syndrome. All of the tumours had an incidence rate <2 per 100 000 pregnancies. Clinical symptoms were similar to those in non-pregnant women due to the hormones released. All women had severe hypertension, and in those diagnosed in pregnancy prior to conception. There was a significantly increased risk of adverse pregnancy outcomes in affected women, with increased rates of stillbirth, preterm labour and operative delivery. CONCLUSIONS: Adrenal tumours are associated with increased risks for pregnant women and their babies. Data on these tumours to inform practice are limited and international collaborative efforts are likely to be needed. TWEETABLE ABSTRACT: Study of hormone-secreting adrenal tumours in pregnancy linked with high BP and high rates of fetal morbidity.