Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation.

Acute intestinal inflammation involves early accumulation of neutrophils (PMNs) followed by either resolution or progression to chronic inflammation. Based on recent evidence that mucosal metabolism influences disease outcomes, we hypothesized that transmigrating PMNs influence the transcriptional profile of the surrounding mucosa. Microarray studies revealed a cohort of hypoxia-responsive genes regulated by PMN-epithelial crosstalk. Transmigrating PMNs rapidly depleted microenvironmental O2 sufficiently to stabilize intestinal epithelial cell hypoxia-inducible factor (HIF). By utilizing HIF reporter mice in an acute colitis model, we investigated the relative contribution of PMNs and the respiratory burst to "inflammatory hypoxia" in vivo. CGD mice, lacking a respiratory burst, developed accentuated colitis compared to control, with exaggerated PMN infiltration and diminished inflammatory hypoxia. Finally, pharmacological HIF stabilization within the mucosa protected CGD mice from severe colitis. In conclusion, transcriptional imprinting by infiltrating neutrophils modulates the host response to inflammation, via localized O2 depletion, resulting in microenvironmental hypoxia and effective inflammatory resolution.

Impact of obstructive sleep apnoea on cognitive function in multiple sclerosis: A longitudinal study.

Cognitive impairment (CI) and fatigue are common in people with multiple sclerosis (MS), with well-known profound effects on quality of life. Sleep disorders, including obstructive sleep apnoea (OSA), are also common in MS patients. The presence of CI has previously been shown to strongly correlate with OSA diagnosed using polysomnography in MS. Treatment of OSA has not previously been investigated as a potential modality to improve cognition in MS patients. Therefore, we sought to investigate the potential effects of OSA treatment on both cognitive function and fatigue in MS patients. Twenty-three participants with MS reporting significant fatigue were enrolled. CI was assessed by the Brief International Cognitive Assessment in MS and the 3-second Paced Auditory Serial Addition Test. All participants underwent overnight polysomnography to assess for possible OSA. Cognitive and fatigue measures were repeated in those subsequently treated for OSA and in a comparative untreated sample. Seven participants (30%) had a diagnosis of OSA based on an apnoea-hypopnea index greater than 5 per hour, with no correlation between the presence of CI and OSA. Verbal learning at follow-up assessment was seen to improve significantly in those treated for OSA, compared with those who were not treated for a sleep disorder. This small study demonstrates the potential for OSA treatment to improve verbal learning in people with MS, larger studies are indicated to further investigate the potential for cognitive and fatigue improvement in people with MS through treatment of comorbid OSA.

Obesity and sleep: a growing concern.

PURPOSE OF REVIEW: The 'obesity epidemic' is a growing concern globally, and obesity trends are projected to continue increasing in both prevalence and overall mean BMI. Cardiovascular and metabolic comorbidities have historically been well described; however, obesity-related respiratory disease is now increasingly prevalent, in particular, sleep disordered breathing. The surge in clinically significant obstructive sleep apnoea and obesity hypoventilation syndrome is associated with increased cardiopulmonary morbidity, quality-of-life impairment, and a potential rise in the frequency of road traffic accidents. RECENT FINDINGS: We discuss recent trends in obesity and obesity-related sleep disordered breathing. We also discuss recently published international guidelines regarding the diagnosis and management of sleep disordered breathing, and in particular, the role of weight management interventions, such as bariatric surgery, in this area. We discuss possible approaches to meet the growing demand for sleep assessment and management in the future. SUMMARY: Obesity-related respiratory disease reflects an increasing proportion of patients in both inpatient and outpatient settings. It is important to recognize the impact of obesity on pulmonary physiology in order to appropriately care for this population, as well as plan for the future.

Risk and Planning in Agriculture: How Planning on Dairy Farms in Ireland Is Affected by Farmers' Regulatory Focus.

This article examines how planning on dairy farms is affected by farmers' motivation. It argues that farmers' choice of expansion strategies can be specified in terms of risk decision making and understood as either prevention-focused or promotion-focused motivation. This relationship was empirically examined using mediated regression analyses where promotion/prevention focus was the independent variable and its effect on total milk production via planned expansion strategies was examined. The results indicate that promotion focus among farmers has an indirect effect on farm expansion via planning strategies that incur greater risk to the farm enterprise. Regulatory focus on the part of farmers has an influence on farmers' planning and risk management activities and must be accounted for in the design and implementation of policy and risk management tools in agriculture.

Severity of obstructive sleep apnoea predicts coronary artery plaque burden: a coronary computed tomographic angiography study.

Obstructive sleep apnoea (OSA) is associated with significantly increased risk of cardiovascular disease. Carotid ultrasonography and retrospective, uncontrolled, coronary imaging studies have suggested an association of OSA with subclinical atherosclerosis, but there is a lack of prospective, controlled studies directly evaluating the relationship of OSA with occult coronary artery disease. We performed coronary computed tomographic angiography and inpatient-attended sleep studies on a cohort of otherwise healthy males attending our sleep laboratory, and compared coronary artery plaque volume between subjects with low and high apnoea/hypopnoea index (AHI) scores. 29 subjects participated. The median AHI was 15.5 events · h(-1), with subjects who scored above this classified as high AHI. No significant differences were observed in demographic, anthropometric and clinical variables between the high- and low-AHI groups. Coronary plaque volume was significantly greater in the high-AHI group (mean plaque volume 2.6 ± 0.7 mm(2) versus 0.8 ± 0.2 mm(2); p=0.017) and, furthermore, correlated significantly with AHI (Spearman's r=0.433; p=0.019). Following adjustment for dyslipidaemia and fasting plasma glucose levels, AHI remained a significant predictor of plaque volume (standardised ß=0.424; p=0.027). In this prospective case-control study, we found that severity of OSA may predict occult coronary atherosclerosis in otherwise healthy overweight or obese male subjects.

An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia.

Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-κB. Recent studies have revealed a high degree of interdependence between HIF and NF-κB signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-κB to demonstrate that hypoxia activates NF-κB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-κB, we confirm a unidirectional dependence of hypoxic HIF-1α accumulation upon an intact canonical NF-κB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-κB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-κB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1α and the p65 subunit of NF-κB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-κB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.

How financial mechanisms can incentivize provision of ecosystem services from land restoration: A systematic review protocol.

The current food chain both contributes to, and is affected by, climate change. While GHG emissions and emissions to water and soil are a problem for the whole food chain, the majority of such emissions and the major solutions to them can be found in the farming and land use sector. The farming system needs to reduce its greenhouse-gas emissions and adapt its supply chain to cope with climate change. A broad variety of payment tools have been proposed to motivate farmers and landowners to take certain actions to reduce greenhouse gas emissions and encourage the protection or restoration of natural resources. The protocol described here (OSF preregistration https://doi.org/10.17605/OSF.IO/STGQ6) outlines the methodology for a systematic review to explore how financial mechanisms such as green bonds can provide incentives to agri-food sector to support environmental sustainability and ecosystem service delivery through land-use change. Our primary research question is: how do financial mechanisms incentivize land restoration? Studies will be categorized according to the types of financial mechanisms, their characteristics, methods of land restoration and their impact on mitigating agri-food footprint. The results are expected to increase our understanding about the design of financing tools currently used to accelerate nature restoration. Moreover, they will inform us about the effectiveness of deploying such tools on rural communities, food companies and landowners.

PGC-1alpha is coupled to HIF-1alpha-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells.

Mitochondrial biogenesis occurs in response to increased cellular ATP demand. The mitochondrial electron transport chain requires molecular oxygen to produce ATP. Thus, increased ATP generation after mitochondrial biogenesis results in increased oxygen demand that must be matched by a corresponding increase in oxygen supply. We found that overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which increases mitochondrial biogenesis in primary skeletal muscle cells, leads to increased expression of a cohort of genes known to be regulated by the dimeric hypoxia-inducible factor (HIF), a master regulator of the adaptive response to hypoxia. PGC-1alpha-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1alpha mRNA but through HIF-1alpha protein stabilization. It occurs because of intracellular hypoxia as a result of increased oxygen consumption after mitochondrial biogenesis. Thus, we propose that at physiologic oxygen concentrations, PGC-1alpha is coupled to HIF signaling through the regulation of intracellular oxygen availability, allowing cells and tissues to match increased oxygen demand after mitochondrial biogenesis with increased oxygen supply.

A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury.

Nitric oxide (NO(*)) competitively inhibits oxygen consumption by mitochondria at cytochrome c oxidase and S-nitrosates thiol proteins. We developed mitochondria-targeted S-nitrosothiols (MitoSNOs) that selectively modulate and protect mitochondrial function. The exemplar MitoSNO1, produced by covalently linking an S-nitrosothiol to the lipophilic triphenylphosphonium cation, was rapidly and extensively accumulated within mitochondria, driven by the membrane potential, where it generated NO(*) and S-nitrosated thiol proteins. MitoSNO1-induced NO(*) production reversibly inhibited respiration at cytochrome c oxidase and increased extracellular oxygen concentration under hypoxic conditions. MitoSNO1 also caused vasorelaxation due to its NO(*) generation. Infusion of MitoSNO1 during reperfusion was protective against heart ischemia-reperfusion injury, consistent with a functional modification of mitochondrial proteins, such as complex I, following S-nitrosation. These results support the idea that selectively targeting NO(*) donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury.

Obesity in Adults: A 2022 Adapted Clinical Practice Guideline for Ireland.

BACKGROUND: This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. SUMMARY: It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients' lived experiences; move beyond simplistic approaches of "eat less, move more" and address the root drivers of obesity. KEY MESSAGES: People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay.

Nasal pillows as an alternative interface in patients with obstructive sleep apnoea syndrome initiating continuous positive airway pressure therapy.

Side-effects directly due to the nasal mask are common in patients with obstructive sleep apnoea syndrome (OSAS) commencing continuous positive airway pressure (CPAP). Recently, nasal pillows have been designed to overcome these issues. Limited evidence exists of the benefits and effectiveness of these devices. Twenty-one patients (19 male, 49±10years) with the established diagnosis of OSAS [apnoea/hypopnoea index (AHI): 52±22] and who had a successful CPAP titration were commenced on CPAP therapy (10±2cmH2O), and randomized to 4weeks of a nasal pillow (P) and a standard nasal mask (M) in a crossover design. Outcome measures were objective compliance, AHI, quality of life, Epworth Sleepiness Score (ESS) and CPAP side-effects. There was no difference in compliance (M versus P: 5.1±1.9h versus 5.0±1.7h; P=0.701) and AHI (2.6±2.7 versus 3.0±2.9; P=0.509). Quality of life and ESS improved with CPAP, but there was no difference in the extent of improvement between both devices. Usage of nasal pillows resulted in less reported pressure on the face and more subjects found the nasal pillow the more comfortable device. However, there was no clear overall preference for either device at the end of the study (mask=57%, pillow=43%; P=0.513). The applied CPAP pressure did not correlate with compliance, AHI and ESS. Furthermore, no differences in outcome parameters were noted comparing groups with CPAP pressure <10 and ≥10cm H(2) O. Nasal pillows are equally effective in CPAP therapy, but do not generally lead to improved compliance.

Continuous positive airway pressure therapy: new generations.

Continuous positive airway pressure (CPAP) is the treatment of choice for obstructive sleep apnoea syndrome (OSAS). However, CPAP is not tolerated by all patients with OSAS and alternative modes of pressure delivery have been developed to overcome pressure intolerance, thereby improving patient comfort and adherence. Auto-adjustable positive airway pressure (APAP) devices may be utilised for the long-term management of OSAS and may also assist in the initial diagnosis of OSAS and titration of conventional CPAP therapy. Newer modalities such as C-Flex and A-Flex also show promise as treatment options in the future. However, the evidence supporting the use of these alternative modalities remains scant, in particular with regard to long-term cardiovascular outcomes. In addition, not all APAP devices use the same technological algorithms and data supporting individual APAP devices cannot be extrapolated to support all. Further studies are required to validate the roles of APAP, C-Flex and A-Flex. In the interim, standard CPAP therapy should continue as the mainstay of OSAS management.

Technologic advances in the assessment and management of obstructive sleep apnoea beyond the apnoea-hypopnoea index: a narrative review.

Obstructive sleep apnoea (OSA) is a growing and serious worldwide health problem with significant health and socioeconomic consequences. Current diagnostic testing strategies are limited by cost, access to resources and over reliance on one measure, namely the apnoea-hypopnoea frequency per hour (AHI). Recent evidence supports moving away from the AHI as the principle measure of OSA severity towards a more personalised approach to OSA diagnosis and treatment that includes phenotypic and biological traits. Novel advances in technology include the use of signals such as heart rate variability (HRV), oximetry and peripheral arterial tonometry (PAT) as alternative or additional measures. Ubiquitous use of smartphones and developments in wearable technology have also led to increased availability of applications and devices to facilitate home screening of at-risk populations, although current evidence indicates relatively poor accuracy in comparison with the traditional gold standard polysomnography (PSG). In this review, we evaluate the current strategies for diagnosing OSA in the context of their limitations, potential physiological targets as alternatives to AHI and the role of novel technology in OSA. We also evaluate the current evidence for using newer technologies in OSA diagnosis, the physiological targets such as smartphone applications and wearable technology. Future developments in OSA diagnosis and assessment will likely focus increasingly on systemic effects of sleep disordered breathing (SDB) such as changes in nocturnal oxygen and blood pressure (BP); and may also include other factors such as circulating biomarkers. These developments will likely require a re-evaluation of the diagnostic and grading criteria for clinically significant OSA.

A portable automated assessment tool for sleep apnea using a combined Holter-oximeter.

STUDY OBJECTIVES: Resource limitations have raised interest in portable monitoring systems that can be used by specialist sleep physicians as part of an overall strategy to improve access to the diagnosis of sleep apnea. This study validates a combined electrocardiogram and oximetry recorder (Holter-oximeter) against simultaneous polysomnography for detection of sleep apnea. DESIGN: Prospective study. SETTING: A dedicated sleep disorders unit. PARTICIPANTS: 59 adults presenting for evaluation of suspected sleep apnea. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: An automated algorithm previously developed for sleep apnea detection was applied to the electrocardiogram and oximetry measurements. The algorithm provides (a) epoch-by-epoch estimates of apnea occurrence and (b) estimates of overall per-subject AHI. Using separate thresholds of AHI > or =15 and AHI <5 for defining clinically significant and insignificant sleep apnea, sensitivity, specificity, and likelihood ratios, conditional on positive or negative (but not indeterminate) test results were used to assess agreement between the proposed system and polysomnography. Sensitivity of 95.8% and specificity of 100% was achieved. Positive and negative likelihood ratios were >20 and 0.04 respectively, with 16.7% of subjects having intermediate test results (AHI 5-14/h). Regardless ofAHI, 85.3% of respiratory events were correctly annotated on an epoch-by-epoch basis. AHI underestimation bias was 0.9/h, and the antilogs of log-transformed limits of agreement were 0.3 and 2.7. Correlation between estimated and reference AHI was 0.95 (P <0.001). CONCLUSION: Combined Holter-oximeter monitoring compares well with polysomnography for identifying sleep apnea in an attended setting and is potentially suitable for home-based automated assessment of sleep apnea in a population suspected of having sleep apnea.

Contemporary terrorism: risk perception in the London options market.

Previous studies have a demonstrated a linkage between terrorist attacks and the operation of financial markets. This article focuses on terrorist events carried out over the last five years and examines how they have been perceived among participants on the London financial market. Data from the London options market suggest a high degree of sensitivity to these events. We argue that this sensitivity reveals a vulnerability in the financial markets should the recent trends in terrorist activity continue.

Effects of renal sympathetic denervation on blood pressure, sleep apnoea severity and metabolic indices: a prospective cohort study.

BACKGROUND: Catheter-based renal sympathetic denervation (RSD) significantly reduces blood pressure in patients with resistant hypertension, who commonly have obstructive sleep apnoea (OSA). These patients are considered particularly responsive to the antihypertensive effects of RSD, but additional benefits of metabolic control on sleep apnoea severity have not been thoroughly investigated. METHODS: The effect of RSD was evaluated prospectively in a cohort of patients with OSA (apnoea-hypopnea index (AHI) ≥15 events per hour and an Epworth Sleepiness Scale (ESS) score ≤9) and treatment resistant hypertension. Changes in blood pressure, polysomnographic parameters and metabolic indices were evaluated at baseline and six months post procedure. RESULTS: At baseline, mean office blood pressure was 166.3/92.8 (14.5/11.7) mmHg and mean ambulatory blood pressure was 154.0/87.3 (11.9/8.5) mmHg. At six months post RSD, mean office blood pressure reduced by 6.6/6.5 (1.9/2.0) mmHg (p < 0.05) and mean ambulatory blood pressure reduced by 8.3/6.2 (2.3/2.0) (p < 0.05). The mean AHI at baseline was 21.3 events/h and 20.5 events/h at six months post RSD, with a mean reduction of 0.9 events/h (95% CI -0.7-1.6, p = 0.39). Glucose at two hours/2 h following tolerance testing reduced by 1.14 mmol/L (95% CI 0.22-2.06, p = 0.03) but changes in other metabolic indices were not statistically significant. CONCLUSION: In patients with resistant hypertension and OSA, RSD resulted in modest improvements in blood pressure control, but no significant changes in sleep apnoea severity. Our study showed small increments in glucose tolerance but no significant changes in other markers of carbohydrate or lipid metabolism.

Health policy and the policymaking system: A case study of primary care in Ireland.

In 2001 the Irish government published a reforming policy intended to modernise and expand the delivery of primary care in Ireland. Fifteen years later, the Irish health system remains beset by problems indicative of a fragmented and underdeveloped primary care system. This case study examines the formation and implementation of the 2001 primary care policy and identifies key risk categories within the policymaking process itself that inhibited the timely achievement of policy objectives. Our methodology includes a directed content analysis of the policy formation and implementation documents and the influencing academic literature, as well as semi-structured interviews with key personnel involved in the process. We identify three broad risk categories - power, resources and capability - within the policymaking process that strongly influenced policy formation and implementation. We additionally show that the disjoint between policy formation and policy implementation was a contested issue among those involved in the policy process and provided space for these risks to critically undermine Ireland's primary care policy.