Workplace inhalational hazards remain common worldwide, even though they are ameliorable. Previous American Thoracic Society documents have assessed the contribution of workplace exposures to asthma ...and chronic obstructive pulmonary disease on a population level, but not to other chronic respiratory diseases. The goal of this document is to report an in-depth literature review and data synthesis of the occupational contribution to the burden of the major nonmalignant respiratory diseases, including airway diseases; interstitial fibrosis; hypersensitivity pneumonitis; other noninfectious granulomatous lung diseases, including sarcoidosis; and selected respiratory infections.
Relevant literature was identified for each respiratory condition. The occupational population attributable fraction (PAF) was estimated for those conditions for which there were sufficient population-based studies to allow pooled estimates. For the other conditions, the occupational burden of disease was estimated on the basis of attribution in case series, incidence rate ratios, or attributable fraction within an exposed group.
Workplace exposures contribute substantially to the burden of multiple chronic respiratory diseases, including asthma (PAF, 16%); chronic obstructive pulmonary disease (PAF, 14%); chronic bronchitis (PAF, 13%); idiopathic pulmonary fibrosis (PAF, 26%); hypersensitivity pneumonitis (occupational burden, 19%); other granulomatous diseases, including sarcoidosis (occupational burden, 30%); pulmonary alveolar proteinosis (occupational burden, 29%); tuberculosis (occupational burden, 2.3% in silica-exposed workers and 1% in healthcare workers); and community-acquired pneumonia in working-age adults (PAF, 10%).
Workplace exposures contribute to the burden of disease across a range of nonmalignant lung conditions in adults (in addition to the 100% burden for the classic occupational pneumoconioses). This burden has important clinical, research, and policy implications. There is a pressing need to improve clinical recognition and public health awareness of the contribution of occupational factors across a range of nonmalignant respiratory diseases.
The 12/15-lipoxygenase enzymes react with fatty acids producing active lipid metabolites that are involved in a number of significant disease states. The latter include type 1 and type 2 diabetes ...(and associated complications), cardiovascular disease, hypertension, renal disease, and the neurological conditions Alzheimer’s disease and Parkinson’s disease. A number of elegant studies over the last thirty years have contributed to unraveling the role that lipoxygenases play in chronic inflammation. The development of animal models with targeted gene deletions has led to a better understanding of the role that lipoxygenases play in various conditions. Selective inhibitors of the different lipoxygenase isoforms are an active area of investigation, and will be both an important research tool and a promising therapeutic target for treating a wide spectrum of human diseases.
Redox stress related loss of beta cell function is a feature of diabetes. Exposure of beta cells and islets to inflammatory mediators elevates reactive oxygen species (ROS) and beta cell dysfunction. ...Direct molecular manipulation of NADPH oxidase-1 (NOX-1) has identified a key role for NOX-1 in cytokine-induced beta cell dysfunction. Plasmid driven elevation of NOX-1 resulted in elevated ROS, loss of glucose-stimulated-insulin-secretion and increased apoptosis. These outcomes on beta cell function are analogous to cytokine treatment. In contrast, reduction of NOX-1 expression, by shRNA, conferred protection to beta cells and islets from the damaging effects of inflammatory cytokines. Collectively, these data support the therapeutic potential for NOX-1 inhibition in diabetes.
•NOX-1 is a key mediator of inflammatory cytokine induced beta cell dysfunction.•Expression of NOX-1 protein results in beta cell dysfunction.•Deletion of NOX-1 protein confers protection to inflammatory cytokines.•Inhibition of NOX-1 is a candidate therapeutic target in diabetes.
ObjectiveTo document the demographic risk factors of workers reported to have silicosis in the UK.MethodsAll cases of silicosis reported to the Surveillance of Work-related and Occupational ...Respiratory Disease (SWORD) scheme between January 1996 and December 2017 were classified into one of eight industry categories, and one of five age groups. In addition, to investigate whether there had been any temporal change, mean age and range at diagnosis was plotted for each year. From 2006, data were also available relating to the date of onset of symptoms, allowing a comparison between workers with and without respiratory symptoms.ResultsFor the period between 1996 and 2017, there were 216 cases of silicosis reported. The mean (range) age of those reported was 61 years (23–89), with the majority (98%) being male. Across all industries, 65% of cases were diagnosed in individuals of working age (<65 for men and <60 for women). Silicosis was reported in young workers across all industry groups, with around one in six of all silicosis cases affecting workers under the age of 46 years. There was no clear trend in age of diagnosis with time. Between 2006 and 2017, 81% of 108 workers with silicosis were reported to be symptomatic.ConclusionsSilicosis remains an important health problem in the UK affecting workers of all ages across a wide range of industries traditionally associated with silica exposure.
Abstract
Background
The COVID-19 pandemic had a significant impact on the operations and functionality of the public transport sector in the UK. This paper reflects on the experience of this sector ...through the pandemic period, and considers recommendations for any future mitigations required for either new COVID-19 waves or a different public health emergency.
Methods
Semi-structured interviews were carried out with public transport experts, organisational leaders, workers and passengers in two phases: Phase 1 from January to May 2021, and Phase 2 from December 2021 to February 2022. Interviews were analysed thematically.
Results
Using the ‘What? So What? Now What?’ reflective model, ideas are drawn out to describe (a) what changes occurred, (b) what effects these changes had on service provision as well as perceptions of risk and mitigation and (c) what lessons have been learned and how these findings can feed into pandemic preparedness for the future. Respondent reflections focussed on the importance of communication, leadership, and maintaining compliance.
Conclusions
The wealth of experience gained through the COVID-19 pandemic in the public transport sector is extremely valuable. Through reflection on this experience, specific recommendations are made relating to these factors, covering: maintaining links across industry, access to information and data, understanding of mitigation effectiveness, improving messaging, challenges of behavioural mitigations, and clear lines of accountability. The recommendations made on the basis of this reflective process will help to improve public health strategy within the public transport sector.
Aims/hypothesis
Upregulation of the reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX)-1 in islets and beta cells follows acute exposure to inflammatory cytokines and is concomitant ...with beta cell dysfunction. NOX-1 is a candidate mediator of inflammation-induced beta cell dysfunction. This study aimed to determine whether selective inhibition of NADPH oxidase-1 presents a new strategy to preserve beta cell function.
Methods
Induced beta cell dysfunction was studied in primary human donor islets, isolated mouse islets and murine beta cell lines. Islets and beta cells were stimulated with inflammatory cytokines (TNF-α, IL-1β, IFN-γ). NOX-1 activity was blocked by the selective inhibitor ML171.
Results
Cytokine induction of intracellular ROS was reduced 80% with 1 μmol/l ML171 in murine beta cell lines (
p
< 0.01). Cytokine-induced apoptosis, measured by caspase-3 activation or quantified fluorescence microscopy, was prevented in islets and beta cell lines up to 100% with ML171 in a concentration-dependent manner (
p
< 0.05). Functionally, glucose-stimulated insulin secretion was abolished by cytokine exposure but preserved by ML171 in isolated mouse islets and murine beta cell lines. A feed-forward regulation of NOX-1 in islets and beta cell lines was disrupted by ML171.
Conclusions/interpretation
Stimulation of NOX-1 activity is a major component of inflammatory cytokine-induced beta cell dysfunction. Significant protection of beta cells is conferred with selective inhibition of NOX-1. Suppression of NOX-1 activity may present a new therapeutic strategy to preserve and protect beta cell function in diabetes.
Islet inflammation contributes to beta cell demise in both type 1 and type 2 diabetes. 12-Lipoxygenase (12-LO, gene expressed as
ALOX12
in humans and
12-Lo
in rodents in this manuscript) produces ...proinflammatory metabolites such as 12(
S
)-hydroxyeicosatetraenoic acids through dioxygenation of polyunsaturated fatty acids. 12-LO was first implicated in diabetes when the increase in
12-Lo
expression and 12(
S
)-hydroxyeicosatetraenoic acid was noted in rodent models of diabetes. Subsequently, germline
12-Lo
−/−
was shown to prevent the development of hyperglycemia in mouse models of type 1 diabetes and in high-fat fed mice. More recently, beta cell-specific
12-Lo
−/−
was shown to protect mice against hyperglycaemia after streptozotocin and a high-fat diet. In humans, 12-LO expression is increased in pancreatic islets of autoantibody-positive, type 1 diabetic and type 2 diabetic organ donors. Interestingly, the high expression of
ALOX12
is associated with the alteration in first-phase glucose-stimulated insulin secretion in human type 2 diabetic islets. To further clarify the role of islet 12-LO in diabetes and to validate 12-LO as a therapeutic target of diabetes, we have studied selective pharmacological inhibitors for 12-LO. The compounds we have identified show promise: they protect beta cell lines and human islets from apoptosis and preserve insulin secretion when challenged by proinflammatory cytokine mixture. Currently studies are underway to test the compounds in mouse models of diabetes. This review summarises a presentation given at the ‘Islet inflammation in type 2 diabetes’ symposium at the 2015 annual meeting of the EASD. It is accompanied two other mini-reviews on topics from this symposium (by Simone Baltrusch, DOI:
10.1007/s00125-016-3891-x
and Marc Donath, DOI:
10.1007/s00125-016-3873-z
) and a commentary by the Session Chair, Piero Marchetti (DOI:
10.1007/s00125-016-3875-x
).
Occupational exposure is an important, global cause of respiratory disease. Unlike many other non-communicable lung diseases, the proximal causes of many occupational lung diseases are well ...understood and they should be amenable to control with use of established and effective approaches. Therefore, the risks arising from exposure to silica and asbestos are well known, as are the means of their prevention. Although the incidence of occupational lung disease has decreased in many countries, in parts of the world undergoing rapid economic transition and population growth-often with large informal and unregulated workforces-occupational exposures continue to impose a heavy burden of disease. The incidence of interstitial and malignant lung diseases remains unacceptably high because control measures are not implemented or exposures arise in novel ways. With the advent of innovative technologies, new threats are continually introduced to the workplace (eg, indium compounds and vicinal diketones). In developed countries, work-related asthma is the commonest occupational lung disease of short latency. Although generic control measures to reduce the risk of developing or exacerbating asthma are well recognised, there is still uncertainty, for example, with regards to the management of workers who develop asthma but remain in the same job. In this Review, we provide recommendations for research, surveillance, and other action for reducing the burden of occupational lung diseases.
► Inflammatory cytokines elevate reactive species, 12-LO and induce islet dysfunction. ► NADPH oxidase 1 is induced in islets and beta cell lines by inflammatory cytokines. ► Inhibitors of NADPH ...oxidase preserve markers of beta cell function. ► 12-LO activates islet NOX-1 and inhibitors of 12-LO block cytokine induced NOX-1. ► Integrated pathway of inflammatory cytokine-induced beta cell dysfunction identified.
Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFα, IL-1β, and INFγ) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p<0.05). This pro-inflammatory cytokine cocktail concomitantly induced loss of islet glucose stimulated insulin response (p<0.05), elevated expression of MCP-1 (p<0.01), increased cellular reactive oxygen species (ROS) and induced cell death. Inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, and a dual selective NOX1/4 inhibitor, blocked ROS generation (p<0.01) and induction of MCP-1 (p<0.05) by pro-inflammatory cytokines in beta cells. It has previously been reported that pro-inflammatory cytokine stimulation induces 12-lipoxygenase (12-LO) expression in human islets. 12-Hydroxyeicosatetraenoic acid (12-HETE), a product of 12-LO activity, stimulated NOX-1 expression in human islets (p<0.05). A novel selective inhibitor of 12-LO blocked induction of NOX-1, production of ROS and pro-caspase 3 cleavage by pro-inflammatory cytokines in INS-1 beta cells (p<0.01). Inhibition was not seen with a structurally related but inactive analog. Importantly, islets from human type 2 diabetic donors have an elevated expression of NOX-1 (p<0.05). This study describes an integrated pathway in beta cells that links beta cell dysfunction induced by pro-inflammatory cytokines with 12-lipoxygenase and NADPH oxidase (NOX-1) activation. Inhibitors of this pathway may provide a new therapeutic strategy to preserve beta cell mass in diabetes.
UK local authorities that experienced sustained high levels of COVID-19 between 1st March 2020 and 28th February 2021 were described by the UK Scientific Advisory Group for Emergencies as areas of ...enduring prevalence. This research was carried out in order to examine the views of local authority Directors of Public Health, who played a crucial role in the local response to COVID-19, on reasons for sustained high levels of prevalence in some areas, alongside an investigation of the mitigation strategies that they implemented during the course of the pandemic.
Interviews were conducted with Directors of Public Health in 19 local authority areas across England, between July and November 2021. This included nine areas identified as areas of enduring prevalence and ten 'comparison' areas.
The outcomes of this study suggests that the geographical differences in prevalence rates are strongly influenced by health inequalities. Structural factors including deprivation, employment, and housing, due to their disproportionate impact on specific groups, converged with demographic factors, including ethnicity and age, and vaccination rates, and were identified as the main drivers of enduring prevalence. There are key differences in these drivers both within and, to a lesser extent, between local authorities. Other than these structural barriers, no major differences in facilitators or barriers to COVID-19 mitigation were identified between areas of varying prevalence. The main features of successful mitigation strategies were a locally tailored approach and partnership working involving local authority departments working with local health, community, voluntary and business organisations.
This study is the first to add the voices of Directors of Public Health, who played a crucial role in the local COVID-19 response. Areas of enduring prevalence existed during the pandemic which were caused by a complex mix of structural factors related to inequalities. Participants advised that more research is needed on the effectiveness of mitigation strategies and other measures to reduce the impact of structural inequalities, to better understand the factors that drive prevalence. This would include an assessment of how these factors combine to predict transmission and how this varies between different areas.
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