Civil Servant and Expert Perspectives on Drivers, Values, Challenges and Successes in Adopting Systems Thinking in Policy-Making

The use of systems thinking (ST) to handle complexity and wicked policy problems is gaining traction in government and the Civil Service, but policy-makers and civil servants can encounter several challenges in practice. How best to support them in understanding and applying ST in policy-making is not well understood. This study aims to explore civil servant and expert perspectives on the drivers and values of ST and the challenges, successes and solutions for its adoption in policy-making. We conducted semi-structured interviews with 31 civil servants across 17 UK government departments, agencies and public bodies, and 5 experts skilled in supporting ST use in policy-making. Via thematic analysis, we identified the values, challenges and successes interviewees experienced when implementing ST and their definitions of the term systems thinking. Civil servants were drawn into an ST approach by their academic training and exposure to it in their previous role(s), workshops, networking events and apprenticeships and through appreciating its values. Civil servants provided various interpretations of ST concepts and values with a strong emphasis on ‘complexity’ and ‘interrelationship’. Our analysis identified eight challenge themes for the implementation of ST in policy-making, including (i) ST language and interpretation, (ii) the policy landscape, (iii) government structure and operation, (iv) methodology and technical aspects, (v) capacity and expertise, (vi) conceptualisation, expectations and buy-in, (vii) stakeholders, engagement and collaboration and (viii) evaluation and evidence. Despite the high interest in ST among civil servants across different policy areas within the UK government and the Civil Service, implementation is challenging. Recommendations for implementation include ST language in policy, systems leadership, policy-specific capacity development and evaluation processes for collecting evidence of impacts

Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome.

RATIONALE: Acute respiratory distress syndrome (ARDS) affects over 200000 people annually in the USA. Despite causing severe, and often refractory, hypoxaemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined. METHODS: Using autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls. MAIN RESULTS: Unprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex vivo with granulocyte macrophage colony-stimulating factor were retained on first pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to platelet-activating factor were initially retained but subsequently released such that only 14% remained in the lungs at 40 min. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS compared with perioperative controls and patients with sepsis. CONCLUSIONS: We demonstrated minimal delay and retention of unprimed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then 'deprime' and are re-released into the systemic circulation. Further, we show that this physiological depriming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.This work was supported by the Wellcome Trust, MRC (UK), Papworth Hospital R&D, Intensive Care Society and NIHR Cambridge Biomedical Research Centre.This is the final published version, also available from http://thorax.bmj.com/content/early/2014/04/04/thoraxjnl-2013-204742.full

Incidence and recognition of acute respiratory distress syndrome in a UK intensive care unit.

The reported incidence of ARDS is highly variable (2.5%-19% of intensive care unit (ICU) patients) and varies depending on study patient population used. We undertook a 6-month, prospective study to determine the incidence and outcome of ARDS in a UK adult University Hospital ICU. 344 patients were admitted during the study period, of these 43 (12.5%) were determined to have ARDS. Patients with ARDS had increased mortality at 28 days and 2 years post-diagnosis, and there was under-recognition of ARDS in both medical records and death certificattion. Our findings have implications for critical care resource planning.This is the final version of the article. It first appeared from BMJ Thorax via ://dx.doi.org/10.1136/thoraxjnl-2016-20840

Viscoelastic properties of differentiating blood cells are fate- and function-dependent.

Although cellular mechanical properties are known to alter during stem cell differentiation, understanding of the functional relevance of such alterations is incomplete. Here, we show that during the course of differentiation of human myeloid precursor cells into three different lineages, the cells alter their viscoelastic properties, measured using an optical stretcher, to suit their ultimate fate and function. Myeloid cells circulating in blood have to be advected through constrictions in blood vessels, engendering the need for compliance at short time-scales (minutes), compared to undifferentiated cells. These findings suggest that reduction in steady-state viscosity is a physiological adaptation for enhanced migration through tissues. Our results indicate that the material properties of cells define their function, can be used as a cell differentiation marker and could serve as target for novel therapies

Cardiovascular adaptation to hypoxia and the role of peripheral resistance.

Systemic vascular pressure in vertebrates is regulated by a range of factors: one key element of control is peripheral resistance in tissue capillary beds. Many aspects of the relationship between central control of vascular flow and peripheral resistance are unclear. An important example of this is the relationship between hypoxic response in individual tissues, and the effect that response has on systemic cardiovascular adaptation to oxygen deprivation. We show here how hypoxic response via the HIF transcription factors in one large vascular bed, that underlying the skin, influences cardiovascular response to hypoxia in mice. We show that the response of the skin to hypoxia feeds back on a wide range of cardiovascular parameters, including heart rate, arterial pressures, and body temperature. These data represent the first demonstration of a dynamic role for oxygen sensing in a peripheral tissue directly modifying cardiovascular response to the challenge of hypoxia

Pulmonary endothelial HIF2α\alpha-arginase axis plays an essential role in the development of hypoxia pulmonary hypertension

This is the author accepted manuscript. The final version is available from the Proceedings of the National Academy of Sciences (PNAS) via https://doi.org/10.1073/pnas.1602978113Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodelling. The hypoxia-inducible transcription factors (HIFs), HIF-1$\alpha$ and HIF-2$\alpha$ are known to contribute to the process of hypoxic pulmonary vascular remodelling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2$\alpha$ is a critical regulator of hypoxia-induced pulmonary arterial hypertension (PAH). The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2$\alpha$ deletion. The RVSP of mice lacking HIF-2$\alpha$ in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic wild type (WT) mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1$\alpha$ exposed to hypoxia. Endothelial HIF-2$\alpha$ deletion also protected mice from hypoxia remodelling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2$\alpha$, likewise attenuated many of the pathophysiological symptoms associated with HPH. We propose a mechanism whereby chronic hypoxia enhances HIF-2$\alpha$ stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2$\alpha$ in regulating the pulmonary vascular response to hypoxia.This study was funded by The Wellcome Trust, Papworth Hospital NIHR Cambridge Biomedical Research Centre

The efficacy and mechanism evaluation of treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole (EME-TIPAC): study protocol for a randomised controlled trial

Background: We hypothesise, based upon the findings from our previous trial, that the addition of co-trimoxazole to standard therapy is beneficial to patients with moderate to severe idiopathic pulmonary fibrosis (IPF). We aim to investigate this by assessing unplanned hospitalisation-free survival (defined as time from randomisation to first non-elective hospitalisation, lung transplant or death) and to determine whether any effect relates to changes in infection and/or markers of disease control and neutrophil activity. Methods/design: The EME-TIPAC trial is a double-blind, placebo-controlled, randomised, multicentre clinical trial. A total of 330 symptomatic patients, aged 40 years old or older, with IPF diagnosed by a multidisciplinary team (MDT) according to international guidelines and a FVC ≤ 75% predicted will be enrolled. Patients are randomised equally to receive either two tablets of co-trimoxazole 480 mg or two placebo tablets twice daily over a median treatment period of 27 (range 12–42) months. All patients receive folic acid 5 mg daily whilst on the trial IMP to reduce the risk of bone marrow depression. The primary outcome for the trial is a composite endpoint consisting of the time to death, transplant or first nonelective hospital admission and will be determined from adverse event reporting, hospital databases and the Office of National Statistics with active tracing of patients missing appointments. Secondary outcomes include the individual components of the primary outcome, (1) King’s Brief Interstitial Lung Disease Questionnaire, (2) MRC Dyspnoea Score, (3) EQ5D, (4) spirometry, (5) total lung-diffusing capacity and (6) routine sputum microbiology. Blood will be taken for cell count, biochemistry and analysis of biomarkers including C-reactive protein and markers of disease. The trial will last for 4 years. Recruitment will take place in a network of approximately 40 sites throughout the UK (see Table 1 for a full list of participating sites). We expect recruitment for 30 months, follow-up for 12 months and trial analysis and reporting to take 4 months. Discussion: The trial is designed to test the hypothesis that treating IPF patients with co-trimoxazole will increase the time to death (all causes), lung transplant or first non-elective hospital admission compared to standard care (https://www.nice.org.uk/guidance/cg163), in patients with moderate to severe disease. The mechanistic aims are to investigate the effect on lung microbiota and other measures of infection, markers of epithelial injury and markers of neutrophil activity. Trial registration: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 17464641. Registered on 29 January 2015. Keywords: Idiopathic pulmonary fibrosis, Co-trimoxazole, Forced vital capacity, Mortalit

Functional Redundancy of Class I Phosphoinositide 3-Kinase (PI3K) Isoforms in Signaling Growth Factor-Mediated Human Neutrophil Survival

We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δKOγKO or p110γKO). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect. Likewise, isolated blood neutrophils derived from double knockout PI3K p110δKOγKO mice underwent normal time-dependent constitutive apoptosis and displayed identical GM-CSF mediated survival to wild type cells, but were sensitized to pharmacological inhibition of the remaining PI3K isoforms. Surprisingly, the pro-survival neutrophil phenotype observed in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) was resilient to inactivation of the PI3K pathway

Civil servant and expert perspectives on drivers, values, challenges and successes in adopting systems thinking in policy making

The use of systems thinking (ST) to handle complexity and wicked policy problems is gaining traction in government and the Civil Service, but policy makers and civil servants can encounter several challenges in practice. How best to support them in understanding and applying ST in policy making is not well understood. This study aims to explore civil servant and expert perspectives on the drivers and values of ST and the challenges, successes and solutions for its adoption in policy making. We conducted semi-structured interviews with 31 civil servants across 17 UK government departments, agencies and public bodies, and 5 experts skilled in supporting ST use in policy making. Via thematic analysis, we identified the values, challenges and successes interviewees experienced when implementing ST and their definitions of the term systems thinking. Civil servants were drawn into an ST approach by their academic training and exposure to it in their previous role(s), workshops, networking events and apprenticeships and through appreciating its values. Civil servants provided various interpretations of ST concepts and values with a strong emphasis on ‘complexity’ and ‘interrelationship’. Our analysis identified eight challenge themes for the implementation of ST in policy making, including (i) ST language and interpretation, (ii) the policy landscape, (iii) government structure and operation, (iv) methodology and technical aspects, (v) capacity and expertise, (vi) conceptualisation, expectations and buy-in, (vii) stakeholders, engagement and collaboration and (viii) evaluation and evidence. Despite the high interest in ST among civil servants across different policy areas within the UK government and the Civil Service, implementation is challenging. Recommendations for implementation include ST language in policy, systems leadership, policy-specific capacity development and evaluation processes for collecting evidence of impacts