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ObjectiveTo derive a new maternity early warning score (MEWS) from prospectively collected data on maternity vital signs and to design clinical response pathways with a Delphi consensus exercise.DesignCentile based score development and Delphi informed escalation pathways.SettingPregnancy Physiology Pattern Prediction (4P) prospective UK cohort study, 1 August 2012 to 28 December 2016.ParticipantsPregnant people from the 4P study, recruited before 20 weeks' gestation at three UK maternity centres (Oxford, Newcastle, and London). 841, 998, and 889 women provided data in the early antenatal, antenatal, and postnatal periods.Main outcome measuresDevelopment of a new national MEWS, assigning numerical weights to measurements in the lower and upper extremes of distributions of individual vital signs from the 4P prospective cohort study. Comparison of escalation rates of the new national MEWS with the Scottish and Irish MEWS systems from 18 to 40 weeks' gestation. Delphi consensus exercise to agree clinical responses to raised scores.ResultsA new national MEWS was developed by assigning numerical weights to measurements in the lower and upper extremes (5%, 1%) of distributions of vital signs, except for oxygen saturation where lower centiles (10%, 2%) were used. For the new national MEWS, in a healthy population, 56% of observation sets resulted in a total score of 0 points, 26% a score of 1 point, 12% a score of 2 points, and 18% a score of ≥2 points (escalation of care is triggered at a total score of ≥2 points). Corresponding values for the Irish MEWS were 37%, 25%, 22%, and 38%, respectively; and for the Scottish MEWS, 50%, 18%, 21%, and 32%, respectively. All three MEWS were similar at the beginning of pregnancy, averaging 0.7-0.9 points. The new national MEWS had a lower mean score for the rest of pregnancy, with the mean score broadly constant (0.6-0.8 points). The new national MEWS had an even distribution of healthy population alerts across the antenatal period. In the postnatal period, heart rate threshold values were adjusted to align with postnatal changes. The centile based score derivation approach meant that each vital sign component in the new national MEWS had a similar alert rate. Suggested clinical responses to different MEWS values were agreed by consensus of an independent expert panel.ConclusionsThe centile based MEWS alerted escalation of care evenly across the antenatal period in a healthy population, while reducing alerts in healthy women compared with other MEWS systems. How well the tool predicted adverse outcomes, however, was not assessed and therefore external validation studies in large datasets are needed. Unlike other MEWS systems, the new national MEWS was developed with prospectively collected data on vital signs and used a systematic, expert informed process to design an associated escalation protocol.

The identification of rare heterozygous TREM2 gene variants that increase the susceptibility of developing sporadic Alzheimer’s disease has reinvigorated research into the contribution of neuroinflammation to Alzheimer’s disease pathology and identified the TREM2 signalling pathway as a novel therapeutic target. The aim of this thesis was to identify TREM2-dependent phenotypes that could be used to identify tool compounds capable of restoring the normal function of TREM2 in the absence of functional TREM2 protein. Any identified tool compounds may serve to further elucidate the function of TREM2 in healthy and diseased states, and identify novel downstream therapeutic targets for the treatment of AD. To achieve this aim compounds with the greatest potential of directly or indirectly targeting the TREM2 signalling pathway were selected, primarily, using SPIEDw to match correlated patterns of gene expression within the connectivity map database. Then, the structure and function of our CRISPR TREM2 knockout BV2 microglial cell lines were characterised to identify TREM2-dependent phenotypes that could be utilised for the development of compound screening assays. Finally, the selected compounds were screened in the developed phenotypic assays to identify tool compounds capable of restoring the normal function of TREM2 in the absence of functional TREM2 protein. Characterisation of the CRISPR TREM2 knockout cells showed that the TREM2-deficient cells possessed significantly shorter and fewer microglial processes, and significantly up-regulated uptake of the Toll-like receptor 2 agonist zymosan, relative to TREM2 wild-type cells. Though it has been well characterised that TREM2 regulates TLR-mediated pro-inflammatory cytokine production, the effect of TREM2 on TLR-mediated uptake has not been investigated previously. The identified uptake phenotype was then utilised as the outcome measure for the primary compound screening assay. During the screen, four hit compounds capable of inhibiting the uptake of zymosan in TREM2 knockout cells, whilst having no effect on TREM2 wild-type, were identified. Then, in a secondary compound screen aimed at promoting the formation of microglial processes in the TREM2 knockout cells, two of the hit compounds from the primary screen also significantly increased the formation of microglial processes in TREM2 knockout. Based upon what is known about the pharmacological activity of these two compounds, it was speculated that they were likely mediating their functions through inhibiting the phosphorylation of ERK. Further investigations may determine that these compounds are suitable tools to further investigate the function of TREM2 in other model systems.

As dependency on fossil fuels continues into the 21st century, oil spills and their remediation remain areas of concern. Understanding how crude oil affects marine life, both in dispersed and non-dispersed forms, is crucial to making informed decisions about the application of chemical dispersants. This study investigated the effects of exposure to Louisiana Sweet crude oil alone and in mixture with Corexit ® EC9500 or Finasol ® OSR52 to two generations of Cyprinodon variegatus, the sheepshead minnow. An adult generation was exposed to either an oil-water accommodated fraction (WAF), an oil + Corexit ® chemically-enhanced WAF (CEWAF) or an oil + Finasol ® CEWAF. Adult fish were then spawned and their juvenile (14-day post-hatch) F1 offspring were exposed in an LC50 test to the same WAF or CEWAF. Few significant effects were seen on adult fish health in the acute WAF and CEWAF exposures, and the subsequent survival of the F1 generation was not significantly affected by parental exposure. Total extractable hydrocarbon (TEH) LC50 values in determined for F1 juveniles from non-exposed adults were >1.1 mg/L, 168.8 mg/L, and 13.7 mg/L from oil-WAF, Corexit-CEWAF, and Finasol-CEWAF, respectively. Total extractable hydrocarbon (TEH) LC50 values determined for F1 juveniles from exposed adults were found to be >1.1 mg/L, 160.5 mg/L, and 8.6 mg/L from oil-WAF, Corexit-CEWAF, and Finasol-CEWAF, respectively.

Following a series of inquiries and reports, health has become an increasingly high priority for the Valuing People Now programme and beyond, in local and regional health and social care systems. Programmes at national, regional and local levels are now in place and bringing the results described in this article, including health checks and the local self-assessment framework, but much remains to be done to ensure that positive change is equitable and sustainable across and within the systems and continues to be driven by people with learning disabilities and their families. Changing current health inequalities will continue to require leadership at all levels.

Sugar-sweetened beverages (SSBs) are the primary source of dietary added sugars in children, with high consumption commonly observed in more deprived areas where obesity prevalence is also highest. Associations between SSB consumption and obesity in children have been widely reported. In March 2016, a two-tier soft drinks industry levy (SDIL) on drinks manufacturers to encourage reformulation of SSBs in the United Kingdom was announced and then implemented in April 2018. We examined trajectories in the prevalence of obesity at ages 4 to 5 years and 10 to 11 years, 19 months after the implementation of SDIL, overall and by sex and deprivation. Data were from the National Child Measurement Programme and included annual repeat cross-sectional measurement of over 1 million children in reception (4 to 5 years old) and year 6 (10 to 11 years old) in state-maintained English primary schools. Interrupted time series (ITS) analysis of monthly obesity prevalence data from September 2013 to November 2019 was used to estimate absolute and relative changes in obesity prevalence compared to a counterfactual (adjusted for temporal variations in obesity prevalence) estimated from the trend prior to SDIL announcement. Differences between observed and counterfactual estimates were examined in November 2019 by age (reception or year 6) and additionally by sex and deprivation quintile. In year 6 girls, there was an overall absolute reduction in obesity prevalence (defined as >95th centile on the UK90 growth charts) of 1.6 percentage points (PPs) (95% confidence interval (CI): 1.1, 2.1), with greatest reductions in the two most deprived quintiles (e.g., there was an absolute reduction of 2.4 PP (95% CI: 1.6, 3.2) in prevalence of obesity in the most deprived quintile). In year 6 boys, there was no change in obesity prevalence, except in the least deprived quintile where there was a 1.6-PP (95% CI: 0.7, 2.5) absolute increase. In reception children, relative to the counterfactual, there were no overall changes in obesity prevalence in boys (0.5 PP (95% CI: 1.0, -0.1)) or girls (0.2 PP (95% CI: 0.8, -0.3)). This study is limited by use of index of multiple deprivation of the school attended to assess individual socioeconomic disadvantage. ITS analyses are vulnerable to unidentified cointerventions and time-varying confounding, neither of which we can rule out. Our results suggest that the SDIL was associated with decreased prevalence of obesity in year 6 girls, with the greatest differences in those living in the most deprived areas. Additional strategies beyond SSB taxation will be needed to reduce obesity prevalence overall, and particularly in older boys and younger children. ISRCTN18042742.

The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.

IntroductionShift work is associated with lung disease and infections. We therefore investigated the impact of shift work on significant COVID-19 illness.Methods501 000 UK Biobank participants were linked to secondary care SARS-CoV-2 PCR results from Public Health England. Healthcare worker occupational testing and those without an occupational history were excluded from analysis.ResultsMultivariate logistic regression (age, sex, ethnicity and deprivation index) revealed that irregular shift work (OR 2.42, 95% CI 1.92 to 3.05), permanent shift work (OR 2.5, 95% CI 1.95 to 3.19), day shift work (OR 2.01, 95% CI 1.55 to 2.6), irregular night shift work (OR 3.04, 95% CI 2.37 to 3.9) and permanent night shift work (OR 2.49, 95% CI 1.67 to 3.7) were all associated with positive COVID-19 tests compared with participants that did not perform shift work. This relationship persisted after adding sleep duration, chronotype, premorbid disease, body mass index, alcohol and smoking to the model. The effects of workplace were controlled for in three ways: (1) by adding in work factors (proximity to a colleague combined with estimated disease exposure) to the multivariate model or (2) comparing participants within each job sector (non-essential, essential and healthcare) and (3) comparing shift work and non-shift working colleagues. In all cases, shift work was significantly associated with COVID-19. In 2017, 120 307 UK Biobank participants had their occupational history reprofiled. Using this updated occupational data shift work remained associated with COVID-19 (OR 4.48 (95% CI 1.8 to 11.18).ConclusionsShift work is associated with a higher likelihood of in-hospital COVID-19 positivity. This risk could potentially be mitigated via additional workplace precautions or vaccination.

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.

Background The UK Soft Drinks Industry Levy (SDIL) was announced in March 2016, became law in April 2017, and was implemented in April 2018. Empirical analyses of commercial responses have not been undertaken to establish the scale, direction or nuance of industry media messaging around fiscal policies. We aimed to develop a detailed understanding of industry reactions to the SDIL in publicly available media, including whether and how these changed from announcement to implementation. Methods We searched Factiva to identify articles related to sugar, soft-drinks, and the SDIL, between 16th March 2016–5 th April 2018. Articles included were UK publications written in English and reporting a quotation from an industry actor in response to the SDIL. We used a longitudinal thematic analysis of public statements by the soft-drinks industry that covered their reactions in relation to key policy milestones. Results Two hundred and ninety-eight articles were included. After the announcement in March 2016, there was strong opposition to the SDIL. After the public consultation, evolving opposition narratives were seen. After the SDIL became law, reactions reflected a shift to adapting to the SDIL. Following the publication of the final regulations, statements sought to emphasise industry opportunities and ensure the perceived profitability of the soft drinks sector. The most significant change in message (from opposition to adapting to the SDIL) occurred when the SDIL was implemented (6 th April 2018). Conclusion Reactions to the SDIL changed over time. Industry modified its media responses from a position of strong opposition to one that appeared to focus on adaptation and maximising perceived profitability after the SDIL became law. This shift suggests that the forces that shape industry media responses to fiscal policies do not remain constant but evolve in response to policy characteristics and the stage of the policy process to maximise beneficial framing.

IntroductionShift work causes misalignment between internal circadian time and the external light/dark cycle and is associated with metabolic disorders and cancer. Approximately 20% of the working population in industrialised countries work permanent or rotating night shifts, exposing this large population to the risk of circadian misalignment-driven disease. Analysis of the impact of shift work on chronic inflammatory diseases is lacking. We investigated the association between shift work and asthma.MethodsWe describe the cross-sectional relationship between shift work and prevalent asthma in >280000 UK Biobank participants, making adjustments for major confounding factors (smoking history, ethnicity, socioeconomic status, physical activity, body mass index). We also investigated chronotype.ResultsCompared with day workers, ‘permanent’ night shift workers had a higher likelihood of moderate-severe asthma (OR 1.23 (95% CI 1.03 to 1.46)). Individuals doing any type of shift work had higher adjusted odds of wheeze/whistling in the chest. Shift workers who never or rarely worked on nights and people working permanent nights had a higher adjusted likelihood of having reduced lung function (FEV1 <80% predicted). We found an increase in the risk of moderate-severe asthma in individuals with extreme chronotypes (morning, OR 1.55 (95% CI 1.06 to 2.27) or evening, OR 1.31 (95%CI 1.22 to 1.40)).ConclusionsThe public health implications of these findings are far-reaching due to the high prevalence and co-occurrence of both asthma and shift work. Future longitudinal follow-up studies are needed to determine if modifying shift work schedules to take into account chronotype might present a public health measure to reduce the risk of developing inflammatory diseases such as asthma.