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OBJECTIVES To describe the patient characteristics, clinical management, and infectious etiology in critically ill children with bronchiolitis. The secondary objective was to determine the association between antibiotic use and hospital length of stay among patients without concomitant bacterial infections. METHODS Retrospective cohort study including patients ≤2 years old with bronchiolitis admitted to 3 Canadian pediatric intensive care units between 2016 and 2018. RESULTS We included 372 patients with a median age of 2.1 months (interquartile range 1.2–6.6) and Pediatric Risk of Mortality III score 3.0 (interquartile range 0–3.0). Initial ventilatory management included high flow nasal cannula (28.2%) and noninvasive positive pressure ventilation (53.7%), of which 41.9% and 87.5%, respectively, did not require escalation of ventilatory support. Chest radiographs (81.7%) and respiratory virus testing (95.4%) were performed in most patients; 14.0% received systemic steroids. Respiratory syncytial virus was detected in 61.3% patients, and 7.5% had a culture-positive concomitant bacterial infection. Of 258 (69.4%) patients with a viral infection, only 45.3% received antibiotics. In this group, antibiotic use beyond 72 hours was not associated with hospital length of stay (ratio 1.14, 95% confidence interval 0.97–1.34). CONCLUSIONS High flow nasal canulae and noninvasive ventilation are commonly used in severe bronchiolitis. Despite contrary evidence, steroids and antibiotics were also frequently used. Evidence-based guidelines specific to children with severe bronchiolitis are needed to improve the care delivered to this patient population.

Background There are approximately 64,000 people living with a diagnosis of dementia in Ireland. This number is expected to double to 150,000 by 2045. The growing need for post diagnostic support has been accentuated by the fact that we are living through an unprecedented Pandemic. Our Dementia Training Network identified the need for a localised educational resource for families supporting those diagnosed with dementia across our service. Methods Following a successful pilot in association with the Alzheimer’s Society of Ireland, staff from the Specialist Memory Service, Integrated Care Team, and Primary Care created a service-informed 6 week course aimed at supporting families. A focus group preceded the first course to establish preferred content. The course delivered education on Dementia; Post Diagnostic Steps; Communication; Non cognitive symptoms; Nutrition & hydration; Assistive Technology; Forward planning and Self-care. The multi-dimensional nature of staff delivering the course creates a rich tapestry of advice and information. All staff involved work together to identify, refer and support families living with dementia in the local area. The group takes place in an accessible location and time which accommodates families. Each course attendee completes a questionnaire prior to and after commencing the group. The level of satisfaction will be measured following every course. Results By the end of 2021, the group will have delivered education and support to 36 families. The automatic referral of all families to this resource will assist in building up confidence to support and enhance self-care. The combined participants from the catchment area will become a network of families joined together on their journey. Conclusion This innovative service collaboration enhances the integrated nature of the Post Diagnostic Care pathway. The Integrated care approach has served to enrich the programme and allow for timely support and advice regarding localised supports.

Background An important consequence of population ageing has been the increasing number of older adults who live alone. According to TILDA data, older adults with the lowest levels of education tend to experience most social isolation and there is a strong association between living alone and loneliness. We sought to compare the cohort of patients open to the Integrated Care for Older Persons (ICPOP) team in a University Teaching Hospital serving a community area of approx. 300,000 population, to this national dataset. Methods A convenience sample of 174 patients who underwent comprehensive geriatric assessment via domiciliary visit between July 2021-May 2022 by was analysed. Data was anonymised and analysis was performed using SPSS v.27. Results The average age was 81.5 (±8.1) with 63% women in the sample. Eighty-five older adults i.e. 49% of the sample either lived alone or spent more than 21 hours alone per 24-hour period. Compared to those who live with someone, those who lived alone had higher rates of likely depression as determined by Geriatric Depression Score (6.6 vs 4.8 p=0.007). They were also likely to have less educational attainment, as determined by years spent in full time education (11.81 vs 10.42 42 p= 0.0016) and those living alone had overall less central heating in their homes than those not living alone (64/85 vs 81/89 p=0.0109). There were no significant differences in the rates of polypharmacy, falls, dementia and home ownership between groups. There were higher levels of frailty in the group living with someone than those living alone as determined by Clinical Frailty Scale (6.14 vs 5.23 p Conclusion A high proportion of patients seen by our ICPOP team live alone and have complex care needs that require an innovative, multidisciplinary approach. Financial vulnerability in this group is likely to compound isolation and loneliness.

Introduction Lack of home ownership is associated higher rates of mental and physical ill-health and death1. According to longitudinal data in Ireland, 92% of persons aged 75 and over own their homes outright with approximately 8% living in rented accommodation2. We sought to compare characteristics of a cohort of patients open to our Integrated Care for Older Persons (ICOP) team with this national Irish dataset. Method A convenience sample of 50 patients reviewed by the ICOP team in a University Teaching Hospital was analysed. Data was anonymised and stored via encrypted key. Analysis was performed using SPSS v.27. Results The average age was 82.5 (±8.1) with 70% women in the sample. There was a lower prevalence of home ownership in this group of patients than the national norm (66% vs 92%) ie 34% were living in rental accommodation, majority Local Authorities. Those living in Local Authority accommodation had lower overall time spent in full time education than those who owned their own home (9.3 ± 3.1 vs 11.5 ± 3.3 p = 0.013), they were more likely to require external assistance with finances (54.5% v 88.2% p = 0.026) and less likely to have a Will (63.6% vs 35.2% p = NS) or EPOA (33.3% vs 23.5% p = 0.053) established. There was no significant difference in age, CFS, MMSE, Waterlow or polypharmacy rates between these groups. Discussion This report highlights a divergence between community dwelling older adults referred to ICOP teams and national standard data. Targeted social work interventions should be operationalised to assist financially vulnerable older adults. 1: Marmot M, Geddes I, Bloomer E, Allen J, Goldblatt P. The health impacts of cold homes and fuel poverty. London: Friends of the Earth. 2011. 2: Orr, J, Scarlett S, Donoghue, O, McGarrigle, C. Housing conditions of Ireland’s older population. Implications for physical and mental health, 2016. Available from https://tilda.tcd.ie/publications/reports/pdf/Report_HousingConditions.pdf

To describe the reasoning processes used by pediatric intensivists to make antibiotic-related decisions.Grounded theory qualitative study.Three Canadian university-affiliated tertiary medical, surgical, and cardiac PICUs.Twenty-one PICU physicians.None.We conducted field observation during morning rounds followed by semistructured interviews with participants to examine the clinical reasoning behind antibiotic-related decisions (starting/stopping antibiotics, or treatment duration) made for patients with a suspected/proven bacterial infection. We used a grounded theory approach for data collection and analysis. Thematic saturation was reached after 21 interviews. Of the 21 participants, 10 (48%) were female, 15 (71%) were PICU attending staff, and 10 (48%) had greater than 10 years in clinical practice. Initial clinical reasoning involves using an analytical approach to determine the likelihood of bacterial infection. In case of uncertainty, an assessment of patient safety is performed, which partly overlaps with the use of intuitive clinical reasoning. Finally, if uncertainty remains, physicians tend to consult infectious diseases experts. Factors that override this clinical reasoning process include disease severity, pressure from consultants, and the tendency to continue antibiotic treatment initiated by colleagues.Antibiotic-related decisions for critically ill children are complex, and pediatric intensivists use several clinical reasoning strategies to decrease the uncertainty around the bacterial etiology of infections. However, disease severity and patient safety concerns may overrule decisions based on clinical evidence and lead to antibiotic use. Several cognitive biases were identified in the clinical reasoning processes.

Background Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. Methods To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. Results We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors’ FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. Conclusion Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. Unravelling the cellular and molecular foundation of human resilience may enable the development of more effective life-support strategies., Graphical abstract Image 1

The endoplasmic reticulum (ER) regulates cellular protein and lipid biosynthesis. ER dysfunction leads to protein misfolding and the unfolded protein response (UPR), which limits protein synthesis to prevent cytotoxicity. Chronic ER stress in skeletal muscle is a unifying mechanism linking lipotoxicity to metabolic disease. Unidentified signals from cells undergoing ER stress propagate paracrine and systemic UPR activation. Here, we induce ER stress and lipotoxicity in myotubes. We observe ER stress-inducing lipid cell non-autonomous signal(s). Lipidomics identifies that palmitate-induced cell stress induces long-chain ceramide 40:1 and 42:1 secretion. Ceramide synthesis through the ceramide synthase 2 de novo pathway is regulated by UPR kinase Perk. Inactivation of CerS2 in mice reduces systemic and muscle ceramide signals and muscle UPR activation. The ceramides are packaged into extracellular vesicles, secreted and induce UPR activation in naïve myotubes through dihydroceramide accumulation. This study furthers our understanding of ER stress by identifying UPR-inducing cell non-autonomous signals.

Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk., Beige and brown fat may influence systemic metabolism through secreted signals. Here the authors identify a panel of metabolites secreted from beige and brown fat cells, which signal to influence fat tissue and skeletal muscle metabolism and have anti-obesity effects in mouse models of obesity and diabetes.

Sandhoff disease (SD) is a lysosomal disease caused by mutations in the gene coding for the β subunit of β-hexosaminidase, leading to deficiency in the enzymes β-hexosaminidase (HEX) A and B. SD is characterised by an accumulation of gangliosides and related glycolipids, mainly in the central nervous system, and progressive neurodegeneration. The underlying cellular mechanisms leading to neurodegeneration and the contribution of inflammation in SD remain undefined. The aim of the present study was to measure global changes in metabolism over time that might reveal novel molecular pathways of disease. We used liquid chromatography-mass spectrometry and 1H Nuclear Magnetic Resonance spectroscopy to profile intact lipids and aqueous metabolites, respectively. We examined spinal cord and cerebrum from healthy and Hexb−/− mice, a mouse model of SD, at ages one, two, three and four months. We report decreased concentrations in lipids typical of the myelin sheath, galactosylceramides and plasmalogen-phosphatidylethanolamines, suggesting that reduced synthesis of myelin lipids is an early event in the development of disease pathology. Reduction in neuronal density is progressive, as demonstrated by decreased concentrations of N-acetylaspartate and amino acid neurotransmitters. Finally, microglial activation, indicated by increased amounts of myo-inositol correlates closely with the late symptomatic phases of the disease.

Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an inter-organ signaling network. Using a metabolomic approach we identified 3-methyl-2-oxovaleric acid (MOVA), 5-oxoproline (5OP), and β-hydroxyisobutyric acid (BHIBA) as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. MOVA, 5OP and BHIBA induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. MOVA and 5OP signal through cAMP-PKA-p38 MAPK and BHIBA via mTOR. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. In humans, plasma and adipose tissue MOVA, 5OP and BHIBA concentrations are correlated with markers of adipose browning and inversely associated with BMI. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.

This chapter concerns claims to the religious in federal Indian law as part of broader claims made in the register of sovereignty. It follows a number of crucial cases that concerned the shape of treaty-protected rights to fishing, hunting, and gathering off-reservation, notably those in the Great Lakes region and the salmon cases in the Pacific Northwest, rulings that cleared the way for the Makah whale hunt. The chapter argues these cases are not simply about political sovereignty or about the economic value of the treaty rights. They are also about the religious and cultural importance of those sacred practices and how the practices themselves constitute peoplehood. It also signals where protecting religion as peoplehood, under international law and especially under federal Indian law, can have its limits, particularly in the short term.

This chapter offers crucial historical context and shows just how freighted the category of religion can be for Native peoples. Religion, or its absence, served as a key instrument in the legalization of the dispossession of North America, first through the legal Doctrine of Christian Discovery, which continues to inform federal Indian law, and second through the criminalization of traditional religions under the federal Indian Bureau's Civilization Regulations from 1883 to 1934. As devastating as the regulations and their assemblage of civilization with a thinly veiled Protestant Christianity were, affected Native people strategically engaged religious freedom discourse to protect those threatened practices that they increasingly argued were their “religions” and protected under religious liberty. Even as the government and missionary sought to curb Native religious practices thought to retard civilization, Euro-Americans began in earnest to fantasize about a Native spirituality that they could collect, admire, and inhabit. But while this awakened Euro-American appreciation for Native cultures served to help lift the formal confines of the Civilization Regulations in the 1930s, it has continued to beset Native efforts to protect collective traditions.

This chapter considers the relative success of court decisions accommodating certain individual Native American inmates in their religious exercise in prisons, especially the sweat lodge. These cases reveal a pattern of what officials refer to as “Native American Spirituality.” In the prison cases, Native American Spirituality emerges as a term of art from corrections management, a line on the intake form for religious preference, and keyed to the language of the federal chaplaincy manual. Prison chaplaincy programs use it in an effort to articulate what's often exceptional and irreducibly diverse about Native religious traditions and to articulate what makes them so difficult to pin down. Especially insofar as the cases largely involve a triad of intertribal practices: sweat lodges, pipe ceremonies, and access to medicinal tobacco, sage, cedar, and sweetgrass.

This chapter discusses repatriation law and a cluster of legal cases involving possession of ceremonial eagle feathers, where courts have consistently affirmed the collective contours of Native religions. Courts have upheld an exemption to the criminal penalties for feather possession tailored to members of federally recognized tribes against legal challenges by individual practitioners of Native religions who are not members of those tribes. These cases illustrate well the difficulties and the possibilities of religion as a category encompassing collective Native traditions. The coalition that persuaded Congress in 1994 to pass the Peyote Amendment to AIRFA was successful in part because it was largely the same circle of advocates, lawyers, tribal spiritual and political leaders, and allies who had recently won congressional passage of two repatriation statutes: the National Museum of the American Indian Act (NMAI) in 1989 and the Native American Graves Protection and Repatriation Act (NAGPRA) the next year. The chapter thus tells the story of Native-led efforts to secure these two laws and offers an interpretation of them not as religious freedom laws, but primarily as additions to federal Indian law that encompass religious and cultural heritage.

This analysis focused on evaluating the environmental consequences of remediation, providing indicators for the environmental quality pillar of 3 "pillars" of the Portland Harbor Sustainability Project (PHSP) framework (the other 2 pillars are economic viability and social equity). The project an environmental impact and benefit analysis (EIBA) and an EIBA-based cost-benefit analysis. Metrics developed in the EIBA were used to quantify and compare remedial alternatives' environmental benefits and impacts in the human and ecological domains, as a result of remedial actions (relative to no action). The cost-benefit results were used to evaluate whether remediation costs were proportionate or disproportionate to the environmental benefits. Alternatives B and D had the highest overall benefit scores, and Alternative F was disproportionately costly relative to its achieved benefits when compared to the other remedial alternatives. Indeed, the costlier alternatives with larger remedial footprints had lower overall EIBA benefit scores-because of substantially more air emissions, noise, and light impacts, and more disturbance to business, recreational access, and habitat during construction-compared to the less costly and smaller alternatives. Put another way, the adverse effects during construction tended to outweigh the long-term benefits, and the net environmental impacts of the larger remedial alternatives far outweighed their small incremental improvements in risk reduction. Results of this Comprehensive Environmental Response Compensation and Liability Act (CERCLA)-linked environmental analysis were integrated with indicators of economic and social impacts of remediation in a stakeholder values-based sustainability framework. These tools (EIBA, EIBA-based cost-benefit analysis, economic impact assessment, and the stakeholder values-based integration) provide transparent and quantitative evaluations of the benefits and impacts associated with remedial alternatives, and should be applied to complex remediation projects to aid environmental decision making. Integr Environ Assess Manag 2018;14:22-31. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Regulatory decisions on remediation should consider affected communities' needs and values, and how these might be impacted by remedial options; this process requires that diverse stakeholders are able to engage in a transparent consideration of value trade-offs and of the distribution of risks and benefits associated with remedial actions and outcomes. The Stakeholder Values Assessment (SVA) tool was developed to evaluate remedial impacts on environmental quality, economic viability, and social equity in the context of stakeholder values and priorities. Stakeholder values were linked to the pillars of sustainability and also to a range of metrics to evaluate how sediment remediation affects these values. Sediment remedial alternatives proposed by the US Environmental Protection Agency (USEPA) for the Portland Harbor Superfund Site were scored for each metric, based upon data provided in published feasibility study (FS) documents. Metric scores were aggregated to generate scores for each value; these were then aggregated to generate scores for each pillar of sustainability. In parallel, the inferred priorities (in terms of regional remediation, restoration, planning, and development) of diverse stakeholder groups (SGs) were used to evaluate the sensitivity and robustness of the values-based sustainability assessment to diverse SG priorities. This approach, which addresses social indicators of impact and then integrates them with indicators of environmental and economic impacts, goes well beyond the Comprehensive Environmental Response, Compensation and Liability Act's (CERCLA) 9 criteria for evaluating remedial alternatives because it evaluates how remedial alternatives might be ranked in terms of the diverse values and priorities of stakeholders. This approach identified trade-offs and points of potential contention, providing a systematic, semiquantitative, transparent valuation tool that can be used in community engagement. Integr Environ Assess Manag 2018;14:43-62. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).