The UK Integrated Assessment Model for source apportionment and air pollution policy applications to PM2.5

Source apportionment and the effect of reducing individual sources is important input for the development of strategies to address air pollution. The UK Integrated Assessment Model, UKIAM, has been developed for this purpose as a flexible framework, combining information from different atmospheric dispersion models to cover different pollutant contributions, and span the range from European to local scale. In this paper we describe the UKIAM as developed for SO2, NOx, NH3, PM2.5 and VOCs. We illustrate its versatility and application with assessment of current PM2.5 concentrations and exposure of the UK population, as a case-study that has been used as the starting point to investigate potential improvement towards attainment of the WHO guideline of 10 µg/m3

Reduced-form and complex ACTM modelling for air quality policy development: a model inter-comparison

Simulation models can be valuable tools in supporting development of air pollution policy. However, exploration of future scenarios depends on reliable and robust modelling to provide confidence in outcomes which cannot be tested against measurements. Here we focus on the UK Integrated Assessment Model, a fast reduced-form model with a purpose to support policy development with modelling of multiple alternative future scenarios, and the EMEP4UK model which is a complex Eulerian Atmospheric Chemistry Transport Model requiring significant computing resources. The EMEP4UK model has been used to model selected core scenarios to compare with UKIAM, and to investigate sensitivity studies such as the interannual variability in response to meteorological differences between years. This model intercomparison addresses total PM2.5, primary PM2.5 and Secondary Inorganic Aerosol concentrations for a baseline of 2018 and selected scenarios for projections to 2040. This work has confirmed the robustness of the UK Integrated Assessment Model for assessing alternative futures through a direct comparison with EMEP4UK. Both models have shown good agreement with measurements, and EMEP4UK shows an ability to replicate past trends. These comparisons highlight how a combination of reduced-form modelling (UKIAM) and complex chemical transport modelling (EMEP4UK) can be effectively used in support of air pollution policy development, informing understanding of projected futures in the context of emerging evidence and uncertainties

PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate

The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2 phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y419 phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP3 signaling, and supports tumor progression

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF.The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF.Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

ECFS best practice guidelines: the 2018 revision

Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast-moving and dynamic field. In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe

Modelling future impacts of air pollution using the multi-scale UK Integrated Assessment Model (UKIAM)

Integrated assessment modelling has evolved to support policy development in relation to air pollutants and greenhouse gases by providing integrated simulation tools able to produce quick and realistic representations of emission scenarios and their environmental impacts without needing to re-run complex atmospheric dispersion models. The UK integrated assessment model has been developed to investigate strategies for reducing UK emissions by integrating information on projected UK emissions of SO2, NOX, NH3, PM10 and PM2.5, atmospheric dispersion, criteria for protection of ecosystems, urban air quality and human health, and data on potential abatement measures to reduce emissions, which may subsequently be linked to associated analyses of costs and benefits. We describe the multi-scale model structure ranging from continental to road-side, UK emissions sources, atmospheric dispersion of emissions, implementation of abatement measures, dynamic integration with European-scale modelling, and environmental impacts. The model generates outputs which are used to evaluate alternative strategies in relation to emissions, deposition patterns, air quality metrics and ecosystem critical load exceedance. Finally, we present a selection of scenarios in relation to the 2020 Business-As-Usual projections and identify potential further reductions beyond those currently being planne

Liminality and transfer to adult services : a qualitative investigation involving young people with cystic fibrosis

The concept of liminality proved useful for thinking about data. Additional work should explore whether it can be applied to different long-term conditions and if initiation rituals vary across services. Nurses could play a role in preparing adolescents by assessing their readiness to transfer on a regular basis and intervening to address individual needs. This would help with young people's shift from a paediatric to adult identity, hopefully preventing them from experiencing a prolonged liminal state post-transfer