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Background: A Strategic Guiding Council (SGC) was created within a Family Carer Decisions Support study, to engage family carers of persons with advanced dementia as advisors to inform the design and implementation of the study. The SGC consists of an international group of family advisors from Canada, the Republic of Ireland, the United Kingdom, the Netherlands, and the Czech Republic. There are limited studies that have explored the integration of Patient and Public Involvement (PPI) in dementia research, end-of-life care and long-term care. Therefore, this study explores PPI engagement in health research with family carers to understand further their interest in being involved in the SCG within the FCDS intervention which is focused on supporting caregivers to make decisions about end-of-life care for residents with advanced dementia., Methods: This study utilized an interpretive descriptive design and explored the motivations of ten family advisors from Canada, the Republic of Ireland, the United Kingdom, and the Netherlands in being part of the SGC. Semi-structured interviews were conducted by phone or videoconferencing and were recorded, transcribed, and analyzed using thematic analysis., Results: Three themes generated from the findings of the study were (1) engaging in reciprocal learning; (2) using lived experience to support other family carers; and (3) creating a collective momentum for advocacy and change., Conclusions: Family carers motivations to being part of the SCG was driven by their intent to help carers navigate the health system and to create a psychosocial support system for other carers experiencing end-of-life with their loved ones. Being part of the SCG provided a benefit to family carers which provided a venue for them to contribute meaningful information from their experience, learn from other health professionals, research and other advisors and an avenue for advocacy work to improve access to end-of-life care supports through education. To our knowledge, this is the first study that explores the motivations of an international group of family advisors' engagement in health research to promote integration of a palliative approach to dementia care in long-term care homes. This study further contributes to the literature from an international perspective the importance of PPI in research. Further research is warranted that explores PPI in research to improve access to end-of-life supports., (© 2024. The Author(s).)

Background: Patient and public involvement (PPI) is a critical priority in research, policy, academia and advocacy organizations. PPI in dementia research is gaining momentum. However, these efforts are missing in international projects aimed at those living with advanced dementia in long-term care (LTC) homes. Additional complexities can arise in enacting PPI within the context of integration of a palliative approach to care and experiences around end-of-life in (EOL) dementia. The mySupport study involved implementing the Family Carer Decision Support (FCDS) intervention for care partners of those living with advanced dementia in LTC in six countries., Research Design and Objective: An interpretive description study was conducted to explore the perspectives of international researchers from six countries on engaging people with lived experiences of dementia and EOL care in research processes. The findings from this study informed the development of a PPI strategy and a subsequent toolkit for the FCDS intervention., Findings: Thirty-eight interviews were completed with project researchers: 12 from the United Kingdom, 8 from Canada, 7 from Ireland, 4 each from Italy and The Netherlands and 3 from the Czech Republic. Four broad themes describe international researchers' perspectives on advancing methods of engagement for people with lived experiences of dementia and EOL in international PPI activities: (1) Groundwork to engage in research; (2) planning for research activities is key; (3) focus on meaningful engagement and (4) having foresight for practical issues shaping PPI., Discussion and Implications: International projects that involve PPI can present many sources of challenges. The findings in this study highlight important considerations for foundational work for incorporating PPI in international projects. Learning from world leaders and those with lived experiences in various regions can be insightful and help share tools and resources., Patient or Public Contribution: PPI was envisioned as a critical part of conducting the mySupport study. The findings from this study informed the development of a PPI strategy and an international Strategic Guiding Council that included family carers of those living with advanced dementia in LTC homes in six countries. This manuscript focused on the perspectives of researchers on their engagement with people with lived experiences of dementia and EOL. The perspectives of persons with lived experiences on engaging in the mySupport research study will be reported in a forthcoming manuscript., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: Long-term care (LTC) homes have been disproportionately impacted during COVID-19., Purpose: To explore the perspectives of stakeholders across Canada around implementing a palliative approach in LTC home during COVID-19., Methods: Qualitative, descriptive design using one-to-one or paired semi-structured interviews., Results: Four themes were identified: (1) the influence of the pandemic on implementing a palliative approach, (2) families are an essential part of implementing a palliative approach, (3) prioritizing advance care planning (ACP) and goals of care (GoC) discussions in anticipation of the overload of deaths and (4) COVID-19 highlighting the need for a palliative approach as well as several subthemes., Conclusion: The COVID-19 pandemic influenced the implementation of a palliative approach to care, where many LTC homes faced an overwhelming number of deaths and restricted the presence of family members. A more concentrated focus on home-wide ACP and GoC conversations and the need for a palliative approach to care in LTC were identified., (© 2023. The Author(s).)

Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects., Objectives: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study., Methods: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge., Results: Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly with lung function and sputum eosinophil counts., Conclusion: Our RNA extraction and profiling protocols allowed reproducible assessments of inflammatory signatures in sputum including quantification of drug effects on this response in allergic asthmatics. This approach offers novel possibilities for the development of pharmacodynamic (PD) biomarkers in asthma.

Background: Allergen-induced late airway response offers important pharmacodynamic targets, including T helper 2 (TH2) biomarkers. However, detection of inflammatory markers has been limited in dithiothreitol-processed sputum., Objectives: To test whether allergen-induced TH2 inflammatory markers can be reproducibly quantified by sensitive detection techniques in ultracentrifuged sputum and the effect of fluticasone (FP) on these endpoints., Methods: Thirteen allergic asthmatics with dual allergen-induced airway responses, documented during a single-blind placebo run-in period, participated in a double-blind, two-period crossover study. Each period consisted of three consecutive days, separated by ≥3 weeks. Following randomization, subjects inhaled FP (500 µg bid, five doses total) or placebo. On Day 2 in each study period, allergen challenge was performed and airway response measured by forced expiratory volume in 1 sec (FEV1) until 7 h post-challenge. Sputum was induced 24 h pre-allergen and 7 and 24 h post-allergen. Sputum samples were split into two portions: TH2 biomarkers were quantified by Meso Scale multiplex platform following ultracentrifugation, and cell differentials were counted on Giemsa-May-Grünwald-stained cytospins. Allergen-induced changes in inflammatory endpoints were compared between FP and placebo using a mixed model ANCOVA., Results: Inhaled allergen induced dual airway responses in all subjects during both placebo periods with reproducible late asthmatic response (LAR) and increased sputum inflammatory biomarkers (IL-2, IL-4, IL-13, and eotaxin-1) and eosinophil counts. FP effectively blunted both the LAR and the inflammatory biomarkers., Conclusions: Combining novel, sensitive quantification methods with ultracentrifugation allows reproducible quantification of sputum biomarkers following allergen challenge, reversed by FP. This approach allows non-invasive identification of pharmacodynamic targets for anti-asthma therapies.

Orphanin FQ/nociceptin (OFQ/N) inhibits the activity of pro-opiomelanocortin (POMC) neurones located in the hypothalamic arcuate nucleus (ARH) that regulate female sexual behaviour and energy balance. We tested the hypothesis that gonadal steroids differentially modulate the ability of OFQ/N to inhibit these cells via presynaptic inhibition of transmitter release and postsynaptic activation of G protein-gated, inwardly-rectifying K(+) (GIRK)-1 channels. Whole-cell patch clamp recordings were performed in hypothalamic slices prepared from ovariectomised rats. OFQ/N (1 μm) decreased the frequency of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs), and also caused a robust outward current in the presence of tetrodotoxin, in ARH neurones from vehicle-treated animals. A priming dose of oestradiol benzoate (EB; 2 μg) increased basal mEPSC frequency, markedly diminished both the OFQ/N-induced decrease in mEPSC frequency and the activation of GIRK-1 currents, and potentiated the OFQ/N-induced decrease in mIPSC frequency. Steroid treatment regimens that facilitate sexual receptivity reinstate the basal mEPSC frequency, the OFQ/N-induced decrease in mEPSC frequency and the activation of GIRK-1 currents to levels observed in vehicle-treated controls, and largely abolish the ability of OFQ/N to decrease mIPSC frequency. These effects were observed in an appreciable population of identified POMC neurones, almost one-half of which projected to the medial preoptic nucleus. Taken together, these data reveal that gonadal steroids influence the pleiotropic actions of OFQ/N on ARH neurones, including POMC neurones, in a disparate manner. These temporal changes in OFQ/N responsiveness further implicate this neuropeptide system as a critical mediator of the gonadal steroid regulation of reproductive behaviour., (© 2014 British Society for Neuroendocrinology.)

Conjugate addition of thiazolidinethiones and oxazolidinethiones to N-crotonylthiazolidinethiones and -oxazolidinethiones was observed in the presence of excess triethylamine in dichloromethane. The addition takes place by the nitrogen of the heterocycle with high diastereoselectivity. It was observed that the stereoselective addition occurs on the anti-s-cis conformation of the N-enoyl sulfur-containing heterocycle.

Precision and accuracy of the quantitative magnetic resonance (QMR) system for measuring fat in phantoms and total body fat (TBF) in humans were investigated. Measurements were made using phantoms: oil, beef with water, beef with oil, and humans with oil and water. TBF(QMR) in humans was compared with TBF by a four-compartment model (TBF(4C)). The coefficient of variation (CV) for replicate TBF(QMR) was 0.437%. QMR fat was lower at 23 °C vs. 37 °C. The fat increase in QMR phantom studies was consistent with the oil increase. When oil was added with humans, the increase in TBF(QMR) was >250 g for the initial 250 g of oil. With additional oil increments, the increase in TBF(QMR) was consistent with the amount of oil added. When water was added with humans, the TBF(QMR) increased independent of the amount of water added. TBF(QMR) was significantly less (mean ± s.e.) than TBF(4C) (females: -0.68 ± 0.27 kg, males: -4.66 ± 0.62 kg; P = 0.0001), TBF(BV) (females: -1.90 ± 0.40 kg; males: -5.68 ± 0.75 kg; P = 0.0001), and TBF(D2O) for males, but greater for females (1.19 ± 0.43 kg vs. -3.69 ± 0.81 kg for males; P = 0.0003). TBF(QMR) was lower than TBF(iDXA) with the difference greater in males (P = 0.001) and decreased with age (P = 0.011). The strong linear relationships between TBF(QMR) and TBF(4C), TBF(BV), and TBF(D2O) with slopes consistent with unity suggest that modifications are required to improve the accuracy. Should the latter be accomplished, QMR holds promise as a highly precise, rapid, and safe, noninvasive method for estimating the amount of and changes in TBF in overweight and severely obese persons.