Peripheral inflammation is associated with remote global gene expression changes in the brain

Background: Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease or psoriasis, are often further burdened with neuropsychiatric symptoms, such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect of peripheral immune activation on neural circuitry remains unclear. Utilizing transcriptomics in a well-characterized murine model of systemic inflammation, we have started to investigate the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain.<p></p> Methods: Several different systemic and tissue-specific models of peripheral toll-like-receptor-(TLR)-driven (lipopolysaccharide (LPS), lipoteichoic acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in C57BL/6 mice. Whole brain transcriptional profiles were assessed and compared 48 hours after intraperitoneal injection of lipopolysaccharide or vehicle, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis, was validated independently using qPCR. Expression of the same panel of target genes was then investigated in a number of sterile and other TLR-dependent models of peripheral inflammation.<p></p> Results: Microarray analysis of whole brains collected 48 hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain. In addition to acute LPS challenge, ISGs were induced in the brain following both chronic LPS-induced systemic inflammation and Imiquimod-induced skin inflammation. Unique to the brain, this transcriptional response is indicative of peripherally triggered, interferon-mediated CNS inflammation. Similar models of sterile inflammation and lipoteichoic-acid-induced systemic inflammation did not share the capacity to trigger ISG induction in the brain.<p></p> Conclusions: These data highlight ISG induction in the brain as being a consequence of a TLR-induced type I interferon response. As considerable evidence links type I interferons to psychiatric disorders, we hypothesize that interferon production in the brain could represent an important mechanism, linking peripheral TLR-induced inflammation with behavioural changes.<p></p&gt

Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes

Background: Recent years have seen an explosion of research pertaining to biological psychiatry, yet despite subsequent advances in our understanding of neuroimmune communication pathways, how the brain senses and responds to peripheral inflammation remains poorly understood. A better understanding of these pathways may be important for generating novel therapeutics to treat many patients with chronic inflammatory diseases who also suffer from neuropsychiatric comorbidities. Here we have systematically assessed the leukocyte infiltrate to the brain following systemic endotoxin exposure to better understand this novel route of neuroimmune communication. Methods: Mice were injected intraperitoneally with LPS daily for 2, 5 or 7 consecutive days. We systematically interrogated the subsequent induction of chemokine transcription in the brain using TaqMan low-density arrays. A combination of flow cytometry and immunohistochemistry was then used to characterise the accompanying leukocyte infiltrate Result: Repeated LPS challenges resulted in prolonged activation of brain-resident microglia, coupled with an increased local transcription of numerous chemokines. After 2 days of administering LPS, there was a marked increase in the expression of the neutrophil chemoattractants CXCL1 and CXCL2; the monocyte chemoattractants CCL2, CCL5, CCL7 and CCL8; and the lymphocyte chemoattractants CXCL9, CXCL10 and CXCL16. In a number of cases, this response was sustained for several days. Chemokine induction was associated with a transient recruitment of neutrophils and monocytes to the brain, coupled with a sustained accumulation of macrophages, CD8+ T cells, NK cells and NKT cells. Strikingly, neutrophils, monocytes and T cells appeared to extravasate from the vasculature and/or CSF to infiltrate the brain parenchyma. Conclusions: Prolonged exposure to a peripheral inflammatory stimulus triggers the recruitment of myeloid cells and lymphocytes to the brain. By altering the inflammatory or metabolic milieu of the brain, this novel method of immune-to-brain communication may have profound implications for patients with chronic inflammatory diseases, potentially leading to neuropsychiatric comorbidities

Assessing the causal relationship between income inequality and mortality and self-rated health: protocol for systematic review and meta-analysis

Background: Income inequality has been linked to health and mortality. While there has been extensive research exploring the relationship, the evidence for whether the relationship is causal remains disputed. We describe the methods for a systematic review that will transparently assess whether a causal relationship exists between income inequality and mortality and self-rated health. Methods: We will identify relevant studies using search terms relating to income inequality, mortality, and self-rated health (SRH). Four databases will be searched: MEDLINE, ISI Web of Science, EMBASE, and the National Bureau of Economic Research. The inclusion criteria have been developed to identify the study designs best suited to assess causality: multilevel studies that have conditioned upon individual income (or a comparable measure, such as socioeconomic position) and natural experiment studies. Risk of bias assessment of included studies will be conducted using ROBINS-I. Where possible, we will convert all measures of income inequality into Gini coefficients and standardize the effect estimate of income inequality on mortality/SRH. We will conduct random-effects meta-analysis to estimate pooled effect estimates when possible. We will assess causality using modified Bradford Hill viewpoints and assess certainty using GRADE. Discussion: This systematic review protocol lays out the complexity of the relationship between income inequality and individual health, as well as our approach for assessing causality. Understanding whether income inequality impacts the health of individuals within a population has major policy implications. By setting out our methods and approach as transparently as we can, we hope this systematic review can provide clarity to an important topic for public policy and public health, as well as acting as an exemplar for other “causal reviews”

Long term (5 Year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial

<b>Background:</b> Bronchial thermoplasty (BT) is a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle. Treated patients have been followed out to 5 years to evaluate long-term safety of this procedure. <br></br> <br></br> <b>Methods:</b> Patients enrolled in the Asthma Intervention Research Trial were on inhaled corticosteroids ≥200 μg beclomethasone or equivalent + long-acting-beta2-agonists and demonstrated worsening of asthma on long-acting-β2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4 year safety study. Adverse events (AEs) and spirometry data were used to assess long-term safety out to 5 years post-BT. <br></br> <br></br> <b>Results:</b> 45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years respectively. The rate of respiratory adverse events (AEs/subject) was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively,). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in Years 2, 3, 4, and 5 compared to Year 1. The FVC and FEV1 values showed no deterioration over the 5 year period in the BT group. Similar results were obtained for the Control group. <br></br><br></br> <b>Conclusions:</b> The absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FVC and FEV1) over a 5-year period post-BT in this group of patients with moderate to severe asthma support the long-term safety of the procedure out to 5 years

Towards an International Classification for Patient Safety: the conceptual framework

Global advances in patient safety have been hampered by the lack of a uniform classification of patient safety concepts. This is a significant barrier to developing strategies to reduce risk, performing evidence-based research and evaluating existing healthcare policies relevant to patient safety. Since 2005, the World Health Organization's World Alliance for Patient Safety has undertaken the Project to Develop an International Classification for Patient Safety (ICPS) to devise a classification which transforms patient safety information collected from disparate systems into a common format to facilitate aggregation, analysis and learning across disciplines, borders and time. A drafting group, comprised of experts from the fields of patient safety, classification theory, health informatics, consumer/patient advocacy, law and medicine, identified and defined key patient safety concepts and developed an internationally agreed conceptual framework for the ICPS based upon existing patient safety classifications. The conceptual framework was iteratively improved through technical expert meetings and a two-stage web-based modified Delphi survey of over 250 international experts. This work culminated in a conceptual framework consisting of ten high level classes: incident type, patient outcomes, patient characteristics, incident characteristics, contributing factors/hazards, organizational outcomes, detection, mitigating factors, ameliorating actions and actions taken to reduce risk. While the framework for the ICPS is in place, several challenges remain. Concepts need to be defined, guidance for using the classification needs to be provided, and further real-world testing needs to occur to progressively refine the ICPS to ensure it is fit for purpos

Towards an International Classification for Patient Safety: the conceptual framework

Global advances in patient safety have been hampered by the lack of a uniform classification of patient safety concepts. This is a significant barrier to developing strategies to reduce risk, performing evidence-based research and evaluating existing healthcare policies relevant to patient safety. Since 2005, the World Health Organization's World Alliance for Patient Safety has undertaken the Project to Develop an International Classification for Patient Safety (ICPS) to devise a classification which transforms patient safety information collected from disparate systems into a common format to facilitate aggregation, analysis and learning across disciplines, borders and time. A drafting group, comprised of experts from the fields of patient safety, classification theory, health informatics, consumer/patient advocacy, law and medicine, identified and defined key patient safety concepts and developed an internationally agreed conceptual framework for the ICPS based upon existing patient safety classifications. The conceptual framework was iteratively improved through technical expert meetings and a two-stage web-based modified Delphi survey of over 250 international experts. This work culminated in a conceptual framework consisting of ten high level classes: incident type, patient outcomes, patient characteristics, incident characteristics, contributing factors/hazards, organizational outcomes, detection, mitigating factors, ameliorating actions and actions taken to reduce risk. While the framework for the ICPS is in place, several challenges remain. Concepts need to be defined, guidance for using the classification needs to be provided, and further real-world testing needs to occur to progressively refine the ICPS to ensure it is fit for purpose

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Four-dimensional electrical resistivity imaging for monitoring pumping-induced saltwater intrusion in a coastal aquifer

Conventional views of saltwater intrusion (SWI), where a basal saline wedge extends inland below fresh groundwater, can be complicated by the influence of saltwater cells in the upper part of aquifers in areas affected by tidal cycles. Distinguishing the contribution of each saltwater source may prove fundamental for well design and resource management. Application of time-lapse electrical resistivity imaging (ERI) during a 32-h pumping test in a pristine unconfined coastal sand aquifer, affected by strong tidal ranges (>2 m), aimed to evaluate the potential of the method to characterize the source of induced SWI in four dimensions (three dimensions and time). Water level monitoring during the test revealed that at the end of pumping, the upper 2 m of the aquifer had dewatered in the vicinity of the well field, reversing hydraulic gradients between the aquifer and the sea. This induced SI, with mixing models of well head water quality suggesting that saline water contributions to total discharge rose from 4 % to 8 %. ERI results reflected dewatering through an increase in resistivity in the upper 2-6 m of the aquifer, while a decline in resistivity, relative to background conditions, occurred immediately below this, reflecting the migration of saline water through the upper layers of the aquifer to the pumping well. By contrast no change in resistivity occurred at depth, indicating no significant change in contribution from the basal saline water to discharge. Test findings suggest that future water resource development at the site should focus on close monitoring of shallow pumping, or pumping from deeper parts of the aquifer, while more generally demonstrating the value of time-lapse geophysical methods in informing coastal water resource management

The impact of a residential camp on grandchildren raised by grandparents: Grandparents’ perspectives

This research aimed to investigate grandparents’ perspectives on the impact of Leadership and Respite Camps, designed for children being raised by their grandparents, on their grandchildren. In-depth interviews were conducted with 34 grandparents whose grandchildren had participated in 1 of 3 camps held between September 2018 and January 2019, in Perth and the south-west of Western Australia. Findings highlighted how grandcarers’ perceived the camps created unique opportunities for grandchildren to share their experiences in a safe and supportive environment. Grandparents reported significant psychosocial benefits to their grandchild, including feeling they fitted in with their peers and were not alone in experiencing a difficult childhood and adolescence; gaining perspective on their situation and developing a new appreciation for their grandparents; being able to emotionally ‘unblock’ traumatic memories through the sharing of experiences in a safe and supportive camp environment; developing resilience, confidence and self-esteem through participation in challenging activities; and making new friendships. This research provides strong evidence that Leadership and Respite Camps designed for grandchildren being raised by their grandparents deliver significant psychosocial benefits to grandchildren, and offers a solid foundation to advocate for regular camps to address the needs of grandparent-led families