Effect of ICU Strain on Timing of Limitations in Life-Sustaining Therapy and Death

Purpose: The effect of capacity strain in an ICU on the timing of end-of-life decision making is unknown. We sought to determine how changes in strain impact timing of new DNR orders and of death. Methods: Retrospective cohort study of 9,891 patients dying in the hospital following an ICU stay ≥ 72 hours in Project IMPACT, 2001-2008. We examined the effect of ICU capacity strain (measured by standardized census, proportion of new admissions, and average patient acuity) on time to initiation of DNR orders and time to death for all ICU decedents using fixed-effects linear regression. Results: Increases in strain were associated with shorter time to DNR for patients with limitations in therapy (predicted time to DNR 6.11 days for highest versus 7.70 days for lowest quintile of acuity, p=0.02; 6.50 days for highest versus 7.77 days for lowest quintile of admissions, p<0.001), and shorter time to death (predicted time to death 7.64 days for highest versus 9.05 days for lowest quintile of admissions, p<0.001; 8.28 days for highest versus 9.06 days for lowest quintile of census, only in closed ICUs, p=0.006). Time to DNR order significantly mediated relationships between acuity and admissions and time to death, explaining the entire effect of acuity, and 65% of the effect of admissions. There was no association between strain and time to death for decedents without a limitation in therapy. Conclusions: Strains in ICU capacity are associated with end-of-life decision making, with shorter times to placement of DNR orders and death for patients admitted during high-strain days

Achieving consensus on priority items for paediatric palliative care outcome measurement: Results from a modified Delphi survey, engagement with a children’s research involvement group and expert item generation

Background: There is no validated outcome measure for use in children’s palliative care outside sub-Saharan Africa. Stakeholders must be involved in the development of such measures to ensure face and content validity. Aim: To gain expert stakeholder consensus on items for inclusion in a paediatric palliative care outcome measure to establish face and content validity. Design: This study was conducted in two phases following Rothrock and COSMIN guidance on patient-reported outcome measure development. Phase 1: Three-round modified Delphi survey to establish consensus on priority items. Phase 2: Item generation meeting with key stakeholders to develop initial measure versions. A young person’s advisory group was also consulted on priority outcomes. Setting and participants: Delphi survey: Parents and professionals with experience of caring for a child with a life-limiting condition. Young person’s advisory group: young people age 10–20 years. Item generation meeting: bereaved parents, academics and clinicians. Results: Phase 1: Delphi survey (n = 82). Agreement increased from Kendall’s W = 0.17 to W = 0.61, indicating movement towards consensus. Agreement between professional and parent ranking was poor (Cohen’s kappa 0.13). Professionals prioritised physical symptoms, whereas parents prioritised psychosocial and practical concerns. Advisory group: Children (n = 22) prioritised items related to living a ‘normal life’ in addition to items prioritised by adult participants. Phase 2: Five age/developmental stage appropriate child and proxy-reported versions of C-POS, containing 13 items, were drafted. Conclusions: This study highlights the importance and feasibility of involving key stakeholders in PROM item generation, as important differences were found in the priority outcomes identified by children, parents and professionals

Spiritual, religious, and existential concerns of children and young people with life-limiting and life-threatening conditions: A qualitative interview study

Background:Despite being a core domain of palliative care, primary data on spiritual and existential concerns has rarely been collected among children with life-limiting and life-threatening conditions and their families. Existing evidence has tended to focus on the religious aspects among children with cancer.Aim:To identify the spiritual needs of children with life-limiting and life-threatening conditions.Design:Cross-sectional semi-structured, qualitative interview study with children, families and health and social care professionals. Verbatim transcripts were analysed using Framework analysisSetting/participants:Purposively sampled children with life-limiting and life-threatening conditions, their parents and siblings, health and social care professionals recruited from six hospitals and three children’s hospices in the UK, and commissioners of paediatric palliative care services recruited through networks and a national charity.Results:One hundred six participants were interviewed: 26 children (5–17 years), 53 family members (parents/carers of children 0–17 years and siblings (5–17 years)), 27 professionals (health and social care professionals and commissioners of paediatric palliative care). Themes included: living life to the fullest, meaning of life and leaving a legacy, uncertainty about the future, determination to survive, accepting or fighting the future and role of religion. Children as young as 5 years old identified needs or concerns in the spiritual domain of care.Conclusions:Addressing spiritual concerns is essential to providing child- and family-centred palliative care. Eliciting spiritual concerns may enable health and social care professionals to identify the things that can support and enhance a meaningful life and legacy for children and their families

Spiritual, religious, and existential concerns of children and young people with life-limiting and life-threatening conditions: A qualitative interview study

BACKGROUND: Despite being a core domain of palliative care, primary data on spiritual and existential concerns has rarely been collected among children with life-limiting and life-threatening conditions and their families. Existing evidence has tended to focus on the religious aspects among children with cancer. AIM: To identify the spiritual needs of children with life-limiting and life-threatening conditions. DESIGN: Cross-sectional semi-structured, qualitative interview study with children, families and health and social care professionals. Verbatim transcripts were analysed using Framework analysis. SETTING/PARTICIPANTS: Purposively sampled children with life-limiting and life-threatening conditions, their parents and siblings, health and social care professionals recruited from six hospitals and three children's hospices in the UK, and commissioners of paediatric palliative care services recruited through networks and a national charity. RESULTS: One hundred six participants were interviewed: 26 children (5-17 years), 53 family members (parents/carers of children 0-17 years and siblings (5-17 years)), 27 professionals (health and social care professionals and commissioners of paediatric palliative care). Themes included: living life to the fullest, meaning of life and leaving a legacy, uncertainty about the future, determination to survive, accepting or fighting the future and role of religion. Children as young as 5 years old identified needs or concerns in the spiritual domain of care. CONCLUSIONS: Addressing spiritual concerns is essential to providing child- and family-centred palliative care. Eliciting spiritual concerns may enable health and social care professionals to identify the things that can support and enhance a meaningful life and legacy for children and their families

Implementation of child-centred outcome measures in routine paediatric healthcare practice: a systematic review

Background: Person-centred outcome measures (PCOMs) are commonly used in routine adult healthcare to measure and improve outcomes, but less attention has been paid to PCOMs in children’s services. The aim of this systematic review is to identify and synthesise existing evidence of the determinants, strategies, and mechanisms that influence the implementation of PCOMs into paediatric healthcare practice. Methods: The review was conducted and reported in accordance with PRISMA guidelines. Databased searched included CINAHL, Embase, Medline, and PsycInfo. Google scholar was also searched for grey literature on 25th March 2022. Studies were included if the setting was a children’s healthcare service, investigating the implementation or use of an outcome measure or screening tool in healthcare practice, and reported outcomes relating to use of a measure. Data were tabulated and thematically analysed through deductive coding to the constructs of the adapted-Consolidated Framework for Implementation Research (CFIR). Results were presented as a narrative synthesis, and a logic model developed. Results: We retained 69 studies, conducted across primary (n = 14), secondary (n = 13), tertiary (n = 37), and community (n = 8) healthcare settings, including both child self-report (n = 46) and parent-proxy (n = 47) measures. The most frequently reported barriers to measure implementation included staff lack of knowledge about how the measure may improve care and outcomes; the complexity of using and implementing the measure; and a lack of resources to support implementation and its continued use including funding and staff. The most frequently reported facilitators of implementation and continued use include educating and training staff and families on: how to implement and use the measure; the advantages of using PCOMs over current practice; and the benefit their use has on patient care and outcomes. The resulting logic model presents the mechanisms through which strategies can reduce the barriers to implementation and support the use of PCOMs in practice. Conclusions: These findings can be used to support the development of context-specific implementation plans through a combination of existing strategies. This will enable the implementation of PCOMs into routine paediatric healthcare practice to empower settings to better identify and improve child-centred outcomes. Trial registration: Prospero CRD 42022330013

Regulating E-Cigarettes: Why Policies Diverge

This paper, part of a festschrift in honor of Professor Malcolm Feeley, explores the landscape of e-cigarette policy globally by looking at three jurisdictions that have taken starkly different approaches to regulating e-cigarettes—the US, Japan, and China. Each of those countries has a robust tobacco industry, government agencies entrusted with protecting public health, an active and sophisticated scientific and medical community, and a regulatory structure for managing new pharmaceutical, tobacco, and consumer products. All three are signatories of the World Health Organization’s Framework Convention on Tobacco Control, all are signatories of the Agreement on Trade-Related Aspects of Intellectual Property Rights, and all are members of the World Trade Organization. Which legal, economic, social and political differences between the three countries explain their diverse approaches to regulating e-cigarettes? Why have they embraced such dramatically different postures toward e-cigarettes? In seeking to answer those questions, the paper builds on Feeley\u27s legacy of comparative scholarship, policy analysis, and focus on law in action

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery