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Abstract Rationale 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. Methods 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. Results 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%). Conclusions 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.

Pathology driving β-cell loss in diabetes is poorly defined. Chronic subclinical inflammation is associated with β-cell dysfunction. Acute in vitro exposure of islets and β-cells to an inflammatory cytokine cocktail (IL-1β/TNF-α/IFN-γ) results in loss of cell function and viability. The contribution of each cytokine alone or in combination has been evaluated in homogeneous mouse β-cell lines and primary mouse islets. Cytokine cooperation is required for β-cell apoptosis with the most potent combinations including IL-1β. Single cytokine exposure did not induce β-cell apoptosis. Expression of endogenous interleukin-12 in β-cells correlated with inflammatory cytokine combinations that induced β-cell apoptosis. Uncoupling of the IL-12 axis by a block of IL-12 production, inhibition of IL-12 receptor/ligand interaction or disruption of IL-12 receptor signaling conferred protection to β-cells from apoptosis induced by inflammatory cytokine stimulation. Signaling through STAT4 is indicated since disruption of IL-12 concomitantly reduced inflammatory cytokine stimulation of endogenous IFN-γ expression. Primary mouse islets isolated from mice deficient in STAT4 show resistance to inflammatory-cytokine-induced cell death when compared to islets isolated from wild type mice. Collectively, the data identify IL-12 as an important mediator of inflammation induced β-cell apoptosis. Modulation of IL-12/STAT4 signaling may be a valuable therapeutic strategy to preserve islet/β-cell viability in established 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.

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.

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.

Background 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. Methods 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. Results 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. Conclusions 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.

ContextThe 12-lipoxygenase (12-LO) pathway produces proinflammatory metabolites, and its activation is implicated in islet inflammation associated with type 1 and type 2 diabetes (T2D).ObjectivesWe aimed to test the efficacy of ML355, a highly selective, small molecule inhibitor of 12-LO, for the preservation of islet function.DesignHuman islets from nondiabetic donors were incubated with a mixture of tumor necrosis factor α , interluekin-1β, and interferon-γ to model islet inflammation. Cytokine-treated islets and human islets from T2D donors were incubated in the presence and absence of ML355.Setting In vitro study.ParticipantsHuman islets from organ donors aged >20 years of both sexes and any race were used. T2D status was defined from either medical history or most recent hemoglobin A1c value >6.5%.InterventionGlucose stimulation.Main Outcome MeasuresStatic and dynamic insulin secretion and oxygen consumption rate (OCR).ResultsML355 prevented the reduction of insulin secretion and OCR in cytokine-treated human islets and improved both parameters in human islets from T2D donors.ConclusionsML355 was efficacious in improving human islet function after cytokine treatment and in T2D islets in vitro. The study suggests that the blockade of the 12-LO pathway may serve as a target for both form of diabetes and provides the basis for further study of this small molecule inhibitor in vivo.A small molecule inhibitor of 12-lipoxygenase improved insulin secretion and oxygen consumption in human islets treated with proinflammatory cytokines or those from type 2 diabetic donors.

Aims/hypothesis Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage. Methods Mouse beta cell lines and mouse and human islets were treated with inflammatory cytokines IL-1β, TNFα and IFNγ in the absence or presence of novel selective 12-lipoxygenase inhibitors. Glucose-stimulated insulin secretion (GSIS), gene expression, cell survival and 12- S -hydroxyeicosatetraenoic acid (12-S-HETE) levels were evaluated using established methods. Pharmacokinetic analysis was performed with the lead inhibitor in CD1 mice. Results Inflammatory cytokines led to the loss of human beta cell function, elevated cell death, increased inflammatory gene expression and upregulation of 12-lipoxygenase expression and activity (measured by 12-S-HETE generation). Two 12-lipoxygenase inhibitors, Compounds 5 and 9, produced a concentration-dependent reduction of stimulated 12-S-HETE levels. GSIS was preserved in the presence of the 12-lipoxygenase inhibitors. 12-Lipoxygenase inhibition preserved survival of primary mouse and human islets. When administered orally, Compound 5 reduced plasma 12-S-HETE in CD1 mice. Compounds 5 and 9 preserved the function and survival of human donor islets exposed to inflammatory cytokines. Conclusions/interpretation Selective inhibition of 12-lipoxygenase activity confers protection to beta cells during exposure to inflammatory cytokines. These concept validation studies identify 12-lipoxygenase as a promising target in the prevention of loss of functional beta cells in diabetes.

Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. We showed previously that deletion of the 12/15-lipoxygenase enzyme (12/15-LO, Alox15 gene) in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D. 12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD-Alox15(null) macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass. 12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15(null) mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass. These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass.

Pathology driving [beta]-cell loss in diabetes is poorly defined. Chronic subclinical inflammation is associated with [beta]-cell dysfunction. Acute in vitro exposure of islets and [beta]-cells to an inflammatory cytokine cocktail (IL-1[beta]/TNF-[alpha]/IFN-[gamma]) results in loss of cell function and viability. The contribution of each cytokine alone or in combination has been evaluated in homogeneous mouse [beta]-cell lines and primary mouse islets. Cytokine cooperation is required for [beta]-cell apoptosis with the most potent combinations including IL-1[beta]. Single cytokine exposure did not induce [beta]-cell apoptosis. Expression of endogenous interleukin-12 in [beta]-cells correlated with inflammatory cytokine combinations that induced [beta]-cell apoptosis. Uncoupling of the IL-12 axis by a block of IL-12 production, inhibition of IL-12 receptor/ligand interaction or disruption of IL-12 receptor signaling conferred protection to [beta]-cells from apoptosis induced by inflammatory cytokine stimulation. Signaling through STAT4 is indicated since disruption of IL-12 concomitantly reduced inflammatory cytokine stimulation of endogenous IFN-[gamma] expression. Primary mouse islets isolated from mice deficient in STAT4 show resistance to inflammatory-cytokine-induced cell death when compared to islets isolated from wild type mice. Collectively, the data identify IL-12 as an important mediator of inflammation induced [beta]-cell apoptosis. Modulation of IL-12/STAT4 signaling may be a valuable therapeutic strategy to preserve islet/[beta]-cell viability in established diabetes.