Understanding the search for more autonomy in Greater Manchester: an alternative perspective on the politics of devolution in England

Critical social scientific accounts of the confused and inconsistent process of “devolution” in England in recent years have rightly emphasized the place that Greater Manchester and, most recently, the Greater Manchester Combined Authority, has occupied at the forefront of UK metropolitan institutional reform. They typically give little credit, however, to the long-running, independent processes of mobilization and institution-building that have resulted in Greater Manchester achieving this vanguard position. This article challenges the idea that contemporary metropolitan governance in Greater Manchester can be seen merely as a pawn in the hands of a regressive, centralist state or else as an undemocratic vehicle designed to enable a city elite to dominate its metropolitan neighbors. In taking a longer historical perspective than is common to critical accounts, the article demonstrates that metropolitanization in England has not followed a coherent centralizing script and neither has the current Combined Authority been constrained, or chosen, to adopt the narrow economic development logic its critics allege. The latter is exemplified by an empirical examination of the work done in Greater Manchester on the theme of work and health. The article concludes with an assessment of how a fragile and very English form of devolution might develop in the difficult context in which the UK now finds itself, arguing that social scientific analysis can perform much better in identifying ways in which further enhancements of sub-national autonomy can support the realization of progressive social and environmental goals

Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies

Takotsubo cardiomyopathy and sepsis: a systematic review

Takotsubo cardiomyopathy (TTC) is characterized by a systolic dysfunction localized in the apical and medial aspect of the left ventricle. It is usually related to physical or emotional stress. Recent evidence highlighting the role of infection led us to analyze the links between TTC and sepsis. A systematic review of the literature was undertaken to assess any trends in clinical findings, diagnosis, and outcomes in such patients. We identified 23 selected papers reporting a total of 26 patients, having sepsis, in whom TTC occurred. For each case, we collected data identifying population characteristics, source of sepsis, clinical disease description, and the results of cardiovascular investigations. The majority of patients were females (n = 16), mean age was 62.8 (14.0 standard deviation) years, and clinical outcome was favorable in 92.3% of the cases once the management of sepsis was initiated. A better understanding of the mechanisms of sepsis-associated TTC may generate novel strategies to treat the complications of this cardiomyopathy and may even help predict and prevent its occurrence

Whole Systems Approach to Diet and Healthy Weight – A longitudinal Process Evaluation in East Scotland

© Royal Society for Public Health 2023. This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/)Aims: Obesity contributes to morbidity and early mortality, affecting people of all ages and socio-demographic backgrounds. Despite attempts to address obesity, efforts to date have only had limited success. Adopting a Whole Systems Approach (WSA) may potentially address obesity and emphasises complex inter-relating factors beyond individual choice. This study aimed to assess implementation of WSA to diet and healthy weight in two council areas of Scotland, longitudinally exploring enablers and barriers. One area followed a Leeds Beckett WSA model (LBM) of implementation, while the other used a hybrid model incorporating existing working systems. Methods: To assess the process of implementing a WSA, interviews and focus groups were conducted after initiation and one year later. Results: Main enablers included: belief in WSA effectiveness; positive relationships between key personnel; buying at community and national levels; funding availability; the working group responsible for coordinating the system development comprising individuals with diverse expertise; good communication; and existing governance structures. Barriers included: insufficient funding; high staff turnover; inadequate training in WSA methodology; engaging all relevant stakeholders and reverting to ‘old ways’ of non-WSA working. The LBM provided a framework for system setup and generating an action plan. Conclusion: This study provides the first independent longitudinal process evaluation of WSAs that have incorporated Leeds Beckett methodology, and offers insights into how a WSA can be implemented to address diet and healthy weight.Peer reviewe

Can mammogram readers swiftly and effectively learn to interpret first post-contrast acquisition subtracted (FAST) MRI, a type of abbreviated breast MRI? : a single centre data-interpretation study

To assess whether NHS breast screening programme (NHSBSP) mammogram readers could effectively interpret first post-contrast acquisition subtracted (FAST) MRI, for intended use in screening for breast cancer. Eight NHSBSP mammogram readers from a single centre (four who also read breast MRI (Group 1) and four who do not (Group 2)) were given structured FAST MRI reader training (median 4 h: 32 min). They then prospectively interpreted 125 FAST MRIs (250 breasts: 194 normal and 56 cancer) comprising a consecutive series of screening MRIs enriched with additional cancer cases from 2015, providing 2000 interpretations. Readers were blinded to other readers' opinions and to clinical information. Categorisation followed the NHSBSP MRI reporting categorisation, with categories 4 and 5 considered indicative of cancer. Diagnostic accuracy (reference standard: histology or 2 years' follow-up) and agreement between readers were determined. The accuracy achieved by Group 2 (847/1000 (85%; 95% confidence interval (CI) 82-87%)) was 5% less than that of Group 1 (898/1000 (90%; 95% CI 88-92)). Good inter-reader agreement was seen between both Group 1 readers (κ = 0.66; 95% CI 0.61-0.71) and Group 2 readers (κ = 0.63; 95% CI 0.58-0.68). The median time taken to interpret each FAST MRI was Group 1: 34 s (range 3-351) and Group 2: 77 s (range 11-321). Brief structured training enabled multiprofessional mammogram readers to achieve similar accuracy at FAST MRI interpretation to consultant radiologists experienced at breast MRI interpretation. FAST MRI could be feasible from a training-the-workforce perspective for screening within NHSBSP

Whole Systems Approaches to Diet and Healthy Weight: A Scoping Review of Reviews

© 2024 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background Obesity is a global epidemic affecting all age groups, populations, and income levels across continents, though is known to disproportionately affect socioeconomically disadvantaged populations. The causes of obesity are complex, informed by diet and weight practices, but shaped by social, commercial, and environmental factors and government policy. Consequently, a Whole System Approach (WSA) – which considers the many causes of obesity and shifts the focus away from individuals as points of intervention and puts an emphasis on understanding and improving the system in which people live – is required. This scoping review of reviews aims to: determine how WSAs to diet and healthy weight have been implemented and evaluated nationally and internationally; to determine what models or theories have been used to implement WSAs; describe how WSAs have been evaluated; determine if WSAs are effective; and to identify the contribution of the public and/or service users in the development of WSAs. Method Systematic searches were carried out using CINAHL, Scopus, PsycINFO (ProQuest), the Cochrane Library, and MEDLINE. Included review papers were those that focused on the application of a whole system approach to diet and/or healthy weight, and/or reported the theory/model used to implement or simulate this approach. Databases were searched from 1995 to March 2022 using a combination of text and Medical Subject Headings (MeSH terms). In addition, reference sections of identified articles were examined for additional relevant articles. Covidence software was used to screen titles and abstracts from the electronic databases and resolve conflicts. Results A total of 20,308 articles were initially retrieved; after duplicate removal 7,690 unique title and abstracts were reviewed, and 110 articles were selected for full text review. On completion of full text review, 8 review articles were included for data extraction. These included: one umbrella review, four systematic reviews, a rapid review, and two literature reviews (one of which was on strategic reports written for government and public health policy). Evaluations of WSA were mainly process evaluations although health outcomes were assessed in some studies. Several conceptual frameworks or mathematical modelling approaches have been applied to WSAs for diet, healthy weight, and obesity to inform their planning or delivery, and to understand/map the associated systems. Common mathematical approaches include agent based or System Dynamic Modelling. Underlying both conceptual and mathematical models is an understanding how the elements of the complex systems impact each other to affect diet, healthy weight, and obesity. WSA implementations have reported some success in positively impacting health outcomes including reducing Body Mass Index, reducing sugary food intake, and increasing physical activity. Public and user involvement in WSA was not widely reported. Conclusion The application of WSA to diet and healthy weight shows promise, yet the research is lagging behind their implementation. Further robust evidence for using WSA to address diet and healthy weight are required, including incorporating process and outcome evaluations (perhaps using established approaches such as Systems Dynamic Modelling). Furthermore, the analysis of epidemiological data alongside longitudinal process and outcome evaluation regarding the implementation of a WSA is required.Peer reviewe

Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition.

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies

Innate Immunity in Human Embryonic Stem Cells: Comparison with Adult Human Endothelial Cells

Treatment of human disease with human embryonic stem cell (hESC)-derived cells is now close to reality, but little is known of their responses to physiological and pathological insult. The ability of cells to respond via activation of Toll like receptors (TLR) is critical in innate immune sensing in most tissues, but also extends to more general danger sensing, e.g. of oxidative stress, in cardiomyocytes. We used biomarker release and gene-array analysis to compare responses in hESC before and after differentiation, and to those in primary human endothelial cells. The presence of cardiomyocytes and endothelial cells was confirmed in differentiated cultures by immunostaining, FACS-sorting and, for cardiomyocytes, beating activity. Undifferentiated hESC did not respond with CXCL8 release to Gram positive or Gram negative bacteria, or a range of PAMPs (pathogen associated molecular patterns) for TLRs 1-9 (apart from flagellin, an activator of TLR5). Surprisingly, lack of TLR-dependent responses was maintained over 4 months of differentiation of hESC, in cultures which included cardiomyocytes and endothelial cells. In contrast, primary cultures of human aortic endothelial cells (HAEC) demonstrated responses to a broad range of PAMPs. Expression of downstream TLR signalling pathways was demonstrated in hESC, and IL-1β, TNFα and INFγ, which bypass the TLRs, stimulated CXCL8 release. NFκB pathway expression was also present in hESC and NFκB was able to translocate to the nucleus. Low expression levels of TLRs were detected in hESC, especially TLRs 1 and 4, explaining the lack of response of hESC to the main TLR signals. TLR5 levels were similar between differentiated hESC and HAEC, and siRNA knockdown of TLR5 abolished the response to flagellin. These findings have potential implications for survival and function of grafted hESC-derived cells

Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart.

Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches