Performance evaluation of Mexico's health system at the national and subnational level, 1990-2019: an analysis of the Health Access and Quality Index.

OBJECTIVES: This study aimed to comprehensively evaluate Mexico's health system performance from 1990 to 2019 utilising the Health Access and Quality Index (HAQI) as a primary indicator. STUDY DESIGN: A retrospective ecological analysis was performed using data from the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) study and the National Population Council (CONAPO). METHODS: HAQI values for 1990, 2000, 2010, 2015, and 2019 were examined for each state in Mexico and three age groups (young, working, and post-working). Additionally, the marginalisation index was employed to assess inequalities in the HAQI distribution across states. The concentration index of the HAQI for each year was estimated, and the efficiency of states in producing the HAQI was evaluated using a data envelopment approach. RESULTS: Through the analysis of national and subnational data, results indicated an overall improvement in healthcare access and quality during the study period. Although differences in the HAQI value related to state marginalisation decreased from 1990 to 2015, by 2019, the inequality had returned to a level comparable to 2000. Efficiency in producing health (HAQI values) exhibited substantial heterogeneity and fluctuations in the ranking order over time. States such as Nuevo León consistently performed well, while others, such as Guerrero, Chihuahua, Mexico City, and Puebla, consistently underperformed. CONCLUSIONS: The findings from this study emphasise the necessity for nuanced strategies to address healthcare disparities and enhance the overall system performance. The study provides valuable insights for ongoing discussions about the future of Mexico's healthcare system, aiming to inform evidence-based policy decisions and improve the nationwide delivery of healthcare services.

Interventions to reduce inequalities for pregnant women living with disadvantage in high-income countries: an umbrella review protocol.

BACKGROUND: Women who live with disadvantages such as socioeconomic deprivation, substance misuse, poor mental health, or domestic abuse face inequalities in health before, during, and after pregnancy and for their infants through to childhood. Women do not experience these factors alone; they accumulate and interact. Therefore, there is a need for an overview of interventions that work across health and social care and target women at risk of inequalities in maternal or child health. METHODS: Systematic review methodology will be used to identify systematic reviews from high-income countries that describe interventions aiming to reduce inequalities for women who experience social disadvantage during pregnancy. We will describe the range of interventions and their effectiveness in reducing inequalities in maternal or child health. Any individual, hospital, or community-level activity specific to women during the pre-conception, antenatal, or postpartum period up to 1 year after birth will be included, regardless of the setting in which they are delivered. We will search eight electronic databases with the pre-determined search strategy and supplement them with extensive grey literature searches. We will present a narrative synthesis, taking into account the quality assessment and coverage of included studies. DISCUSSION: Inequalities in maternal and child health are a key priority area for national policymakers. Understanding the range and effectiveness of interventions across the perinatal period will inform policy and practice. Identifying gaps in the evidence will inform future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023455502.

Mycobacterial formation of intracellular lipid inclusions is a dynamic process associated with rapid replication.

Intracellular lipid inclusions (ILI) are triacylglyceride rich organelles produced by mycobacteria thought to serve as energy reservoirs. It is believed that ILI are formed as a result of a dosR mediated transition from replicative growth to non-replicating persistence (NRP). ILI rich Mycobacterium tuberculosis (Mtb) bacilli have been reported during infection and in sputum, establishing their importance in Mtb pathogenesis. Studies conducted in mycobacteria such as Mycobacterium smegmatis, Mycobacterium abscessus, or lab Mtb strains have demonstrated ILI formation in the presence of hypoxic, nitric oxide, nutrient limitation, or low nitrogen stress, conditions believed to emulate the host environment within which Mtb resides. Here, we show that M. marinum and clinical Mtb isolates make ILI during active replication in axenic culture independent of environmental stressors. By tracking ILI formation dynamics we demonstrate that ILI are quickly formed in the presence of fresh media or exogenous fatty acids but are rapidly depleted while bacteria are still actively replicating. We also show that the cell envelope is an alternate site for neutral lipid accumulation observed during stationary phase. In addition, we screen a panel of 60 clinical isolates and observe variation in ILI production during early log phase growth between and among Mtb lineages. Finally, we show that dosR expression level does not strictly correlate with ILI accumulation in fresh clinical isolates. Taken together, our data provide evidence of an active ILI formation pathway in replicating mycobacteria cultured in the absence of stressors, suggesting a decoupling of ILI formation from NRP.

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.

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.

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.

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).

The challenges and opportunities for implementing group antenatal care ('Pregnancy Circles') as part of standard NHS maternity care: A co-designed qualitative study.

OBJECTIVE: To identify the challenges and opportunities for rolling out a bespoke model of group antenatal care called Pregnancy Circles (PC) within the National Health Service: what kind of support and training is needed and what adaptations are appropriate, including during a pandemic when face-to-face interaction is limited. DESIGN: Exploratory qualitative study (online focus group). Study co-designed with midwives. Data analysed thematically using an ecological model to synthesise. SETTING: Five maternity services within the National Health Service. PARTICIPANTS: Seven midwives who facilitated PCs. Three senior midwives with implementation experience participated in the co-design process. FINDINGS: Three themes operating across the ecological model were identified: 'Implementing innovation', 'Philosophy of care' and 'Resource management'. Tensions were identified between group care's focus on relationships and professional autonomy, and concepts of efficiency within the NHS's market model of care. Midwives found protected time, training and ongoing support essential for developing the skills and confidence needed to deliver this innovative model of care. Integrating Pregnancy Circles with continuity of carer models was seen as the most promising opportunity for long-term implementation. Midwives perceived continuity and peer support as the most effective elements of the model and there was some evidence that the model may be robust enough to withstand adaptation to online delivery. KEY CONCLUSIONS: Midwives facilitating group care enjoyed the relationships, autonomy and professional development the model offered. Harnessing this personal (micro-level) satisfaction is key to wider implementation. Group care is well aligned with current maternity policy but the challenges midwives face (temporal, practical and cultural) must be anticipated and addressed at macro and meso level for wider implementation to be sustainable. The PC model may be flexible enough to adapt to online delivery and extend continuity of care but further research is needed in these areas. IMPLICATIONS FOR PRACTICE: Implementation of group care in the NHS requires senior leadership and expertise in change management, protected time for training and delivery of the model, and funding for equipment. Training and ongoing support, are vital for sustainability and quality control. There is potential for online delivery and integrating group care with continuity models.

A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability.

It is now over 30 years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. While there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the tryptophan REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides, to multitryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibodies in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating biomolecular simulation with experimental data to yield novel insights.

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.

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.

Reducing the level of nutrition of twin-bearing ewes during mid to late pregnancy produces leaner prime lambs at slaughter.

The Australian prime lamb industry is seeking to improve lean meat yield (LMY) as a means to increasing efficiency and profitability across the whole value chain. The LMY of prime lambs is affected by genetics and on-farm nutrition from birth to slaughter and is the total muscle weight relative to the total carcass weight. Under the production conditions of south eastern Australia, many ewe flocks experience a moderate reduction in nutrition in mid to late pregnancy due to a decrease in pasture availability and quality. Correcting nutritional deficits throughout gestation requires the feeding of supplements. This enables the pregnant ewe to meet condition score (CS) targets at lambing. However, limited resources on farm often mean it is difficult to effectively manage nutritional supplementation of the pregnant ewe flock. The impact of reduced ewe nutrition in mid to late pregnancy on the body composition of finishing lambs and subsequent carcass composition remains unknown. This study investigated the effect of moderately reducing ewe nutrition in mid to late gestation on the body composition of finishing lambs and carcass composition at slaughter on a commercial scale. Multiple born lambs to CS2.5 target ewes were lighter at birth and weaning, had lower feedlot entry and exit weights with lower pre-slaughter and carcass weights compared with CS3.0 and CS3.5 target ewes. These lambs also had significantly lower eye muscle and fat depth when measured by ultrasound prior to slaughter and carcass subcutaneous fat depth measured 110 mm from the spine along the 12th rib (GR 12th) and at the C-site (C-fat). Although carcasses were ~5% lighter, results showed that male progeny born to ewes with reduced nutrition from day 50 gestation to a target CS2.5 at lambing had a higher percentage of lean tissue mass as measured by dual energy X-ray absorptiometry and a lower percentage of fat during finishing and at slaughter, with the multiple born progeny from CS3.0 and CS3.5 target ewes being similar. These data suggest lambs produced from multiple bearing ewes that have had a moderate reduction in nutrition during pregnancy are less mature. This effect was also independent of lamb finishing system. The 5% reduction in carcass weight observed in this study would have commercially relevant consequences for prime lamb producers, despite a small gain in LMY.

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.

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.

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.

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.

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.