Literature review: decision-making regarding slow resuscitation

Aims and objectives. Applying ethical principles as a framework, a review of the literature will be presented regarding the decision‐making process of slow codes. Background. Slow codes are cardiopulmonary resuscitative efforts intentionally conducted too slowly for resuscitation to occur. While some authors argue that a slow code is a non‐maleficent and beneficent act towards the hopelessly ill patient, others believe that this practice is harmful and deceptive, that it disregards patient and surrogate autonomy and deprives the patient of a peaceful death. Method. Literature review. Results. Decision‐making surrounding cardiopulmonary resuscitation receives considerable attention in the literature. However, data relating to the decision‐making process in slow codes is sparse. One ethnographic study described the practice of slow codes as doing good and preventing harm to the patient. Conclusions. It was evident from the literature review that slow codes, even in the most limited form, are invasive and undignified and that they prolong death and suffering. Further research is needed to examine why slow codes happen despite the availability of a do‐not‐resuscitate order. Relevance to clinical practice. Decision‐making regarding cardiopulmonary resuscitation is increasingly problematic in Ireland. The literature review suggests that clinical guidelines regarding decision‐making and cardiopulmonary resuscitation should be introduced to reduce the likelihood of slow codes occurring, but also that nurses and doctors endeavour to communicate more effectively with patients and family.     

Food insecurity works through depression, parenting, and infant feeding to influence overweight and health in toddlers

We used the Early Childhood Longitudinal Study-Birth Cohort 9- and 24-mo surveys (n = 8693) and Structural Equation Modeling to examine direct and indirect associations between food insecurity and toddlers' overweight (weight for length), physical health, and length for age. There were significant effects of food insecurity on parental depression and parental depression in turn influenced physical health. There were also significant effects of food insecurity on parenting practices, which in turn were significantly associated with infant feeding and subsequently toddlers' overweight. There were no significant direct or indirect associations between food insecurity and toddlers' length for age. Our results show that food insecurity influences parenting, including both depression and parenting practices. Findings suggest parental depression is a stressor on parenting behavior that social policy should address to alleviate problematic child health outcomes. Findings underscore the importance of continuing and strengthening policy initiatives to ensure that families with infants and toddlers have sufficient, predictable, and reliable food supply.     

Maintaining dendritic cell viability in culture

When mouse dendritic cells (DCs) are isolated from tissues, purified and placed in a nutritive culture they die more rapidly than would be expected from their normal turnover in vivo. This can distort culture assays of DC function. We therefore tested several approaches to prolonging DC survival in culture. Of several cytokines tested granulocyte-macrophage colony stimulating factor was most effective at preserving the viability of conventional DCs (cDCs) but was ineffective for plasmacytoid DCs (pDCs). Surprisingly, Fms-like tyrosine kinase 3 ligand, crucial for DC development, produced only a marginal improvement in DC survival in culture, and interleukin-3, reported to prevent apoptosis of human pDCs, produced only a minor improvement in survival of mouse DCs. Genetic manipulation of cell death pathways was also tested, to avoid activation effects exerted by cytokine signalling. The isolation of DCs from mice overexpressing Bcl-2 was especially effective in maintaining pDC viability but gave a lesser improvement in cDC viability. DCs isolated from Bim^−/−Noxa^−/− mice also showed improved culture survival, but in this case with pDCs showing the least improvement.     

The human gene damage index as a gene-level approach to prioritizing exome variants

The protein-coding exome of a patient with a monogenic disease contains about 20,000 variants, only one or two of which are disease causing. We found that 58% of rare variants in the protein-coding exome of the general population are located in only 2% of the genes. Prompted by this observation, we aimed to develop a gene-level approach for predicting whether a given human protein-coding gene is likely to harbor disease-causing mutations. To this end, we derived the gene damage index (GDI): a genome-wide, gene-level metric of the mutational damage that has accumulated in the general population. We found that the GDI was correlated with selective evolutionary pressure, protein complexity, coding sequence length, and the number of paralogs. We compared GDI with the leading gene-level approaches, genic intolerance, and de novo excess, and demonstrated that GDI performed best for the detection of false positives (i.e., removing exome variants in genes irrelevant to disease), whereas genic intolerance and de novo excess performed better for the detection of true positives (i.e., assessing de novo mutations in genes likely to be disease causing). The GDI server, data, and software are freely available to noncommercial users from lab.rockefeller.edu/casanova/GDI.Germ-line mutations can contribute to the long-term adaptation of humans, but at the expense of causing a large number of genetic diseases (1). The advent of next-generation sequencing (NGS)-based approaches, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA-Seq, has facilitated the large-scale detection of gene variants at both the individual and population levels (2–6). In patients suffering from a monogenic disease, at most two variants are disease causing [true positives (TP)], and the other 20,000 or so protein-coding exome variants are false positives (FP; type I error). Several variant-level metrics predicting the biochemical impact of DNA mutations (7–9) can be used to prioritize candidate variants for a phenotype of interest (10, 11). Gene-level metrics aim to prioritize the genes themselves, providing information that can be used for the further prioritization of variants. There are currently fewer gene-level than variant-level computational methods. They provide complementary information, as it is best to predict the impact of a variant by also taking into account population genetics data for its locus. Current gene-level methods include genic intolerance, as measured by the residual variation intolerance score (RVIS) (12) and de novo excess (DNE) (13). These metrics are particularly useful for determining whether a given gene (and, by inference, its variants) is a plausible candidate for involvement in a particular genetic disease (i.e., for the selection of a short list of candidate genes and variants, which include the TPs). However, owing to the large number and diversity of variants, the selection of a single candidate gene from the NGS data for a given patient with a specific disease remains challenging.We reasoned that genes frequently mutated in healthy populations would be unlikely to cause inherited and rare diseases, but would probably make a disproportionate contribution to the variant calls observed in any given patient. Conversely, mutations in genes that are never or only rarely mutated under normal circumstances are more likely to be disease-causing. Leading gene-level strategies are based on selective pressure (12) and de novo mutation rate estimates (13). These methods are tailored to detect genes likely to harbor TPs. However, these methods do not directly calculate quantitatively the mutational load for human genes in the general (i.e., “healthy”) population or the frequencies of mutant alleles. These methods may, therefore, not be optimal for filtering out highly mutated genes, which are likely to harbor many FPs. Moreover, there has been no formal comparison of the power of these gene-level methods and their combinations for maximizing the discovery of FPs and TPs by NGS. We therefore aimed to generate a robust metric of the cumulative mutational damage to each human protein-coding gene, to make it easier to distinguish the FP variants harbored by highly damaged genes (e.g., under relaxed constraint or positive selection) from potential candidate genes and variants, including the TPs. By damaged genes, we refer to genes displaying many nonsynonymous mutations, which are not necessarily damaging biochemically or evolutionarily. We developed the gene damage index (GDI), which defines, in silico, the mutational damage accumulated by each protein-coding human gene in the general population, and reflecting the combined influences of drifts and selections. We then tested this approach with the WES data for 84 patients in our in-house database, each of these patients having a known primary immunodeficiency (PID). Finally, we used receiver operating characteristic (ROC) curves for formal comparisons of performance between GDI and the existing gene-level RVIS and DNE approaches, and to assess the power of the gene-level methods for detecting enrichment in de novo mutations in cases versus controls. We also tested whether these methods could act in synergy to filter out FPs and select TPs.     

Underestimating a serving size may lead to increased food consumption when using Canada's Food Guide

It is unclear whether Canadians accurately estimate serving sizes and the number of servings in their diet as intended by Canada's Food Guide (CFG). The objective of this study was to determine if participants can accurately quantify the size of 1 serving and the number of servings consumed per day. White, Black, South Asian, and East Asian adults (n = 145) estimated the quantity of food that constituted 1 CFG serving, and used CFG to estimate the number of servings that they consumed from their 24-h dietary recall. Participants estimated 1 serving size of vegetables and fruit (+43%) and grains (+55%) to be larger than CFG serving sizes (p?≤ 0.05); meat alternatives (-33%) and cheese (-31%) to be smaller than a CFG serving size (p?≤ 0.05); and chicken, carrots, and milk servings accurately (p?> 0.05). Serving size estimates were positively correlated with the amount of food participants regularly consumed at 1 meal (p?< 0.001). From their food records, all ethnicities estimated that they consumed fewer servings of vegetables and fruit (-15%), grains (-28%), and meat and alternatives (-14%) than they actually consumed, and more servings of milk and alternatives (+26%, p?≤ 0.05) than they actually consumed. Consequently, 68% of participants believed they needed to increase consumption by greater than 200?kcal to meet CFG recommendations. In conclusion, estimating serving sizes to be larger than what is defined by CFG may inadvertently lead to estimating that fewer servings were consumed and overeating if Canadians follow CFG recommendations without guidance. Thus, revision to CFG or greater public education regarding the dietary guidelines is warranted.     

Quality or quantity? Exploring the relationship between Public Open Space attributes and mental health in Perth,Western Australia

Mental health is a public health priority globally. Public Open Space (POS) may enhance mental health by facilitating contact with nature and the development of supportive relationships. Despite growing interest in the influence of the built environment on mental health, associations between POS attributes and mental health remain relatively unexplored. In particular, few studies have examined the relative effects of the quantity and quality of POS within a neighbourhood on mental health. Guided by a social-ecological framework, this study investigated the relationship between POS attributes (i.e., quantity and quality) and better mental health (i.e., low risk of psychological distress) in residents of new housing developments in the Perth metropolitan area, Western Australia. The extent to which relationships between POS attributes and mental health were confounded by psychosocial factors (e.g., social support, sense of community) and frequent use of POS was also explored. Data were obtained from a cross-sectional survey (n = 911), a POS audit, and Geographical Information Systems, and was analysed using logistic regression. Approximately 80% of survey participants were at low risk of psychological distress. Residents of neighbourhoods with high quality POS had higher odds of low psychosocial distress than residents of neighbourhoods with low quality POS. This appeared to be irrespective of whether or not they used POS. However, the quantity of neighbourhood POS was not associated with low psychological distress. From a mental health perspective, POS quality within a neighbourhood appears to be more important than POS quantity. This finding has policy implications and warrants further investigation.     

Focal cerebral ischemia preferentially affects neurons distant from their neighboring microvessels.

Developing cerebral infarction obscures the relationship of neurons to their local supply microvessels. We tested the notion that in the basal ganglia (i) an ordered relationship between neurons and their nearest neighboring microvessel exists, and (ii) focal ischemia predictably affects neuron integrity based on microvessel-neuron proximity. Distances between individual microvessels and their nearest neurons ([m-n distance]s) were measured in normal primates and ischemic subjects undergoing middle cerebral artery occlusion for 2 hours. An ordered microvessel-neuron relationship exists in the normal nonischemic basal ganglia within the early hours of focal ischemia. During ischemia normal (n) and sensitive (n*) neurons are interspersed. On average, neurons more distant from their nearest microvessel are most sensitive ([m-n distance]=16.2+/-11.2 microm versus [m-n* distance]=22.2+/-13.0 microm, 2P<0.00000001). Neurons not expressing glutamic acid decarboxylase were more likely to be sensitive than those with a normal microvessel-neuron relationship. In contrast, the [m-n distance] distribution of injured tyrosine hydroxylase-containing neurons was similar to those without tyrosine hydroxylase. Hence, the [m-n distance] relationship in the normal and ischemic basal ganglia is highly ordered, and distant neurons are consistently perturbed by ischemia, although this is not uniformly dependent on neurotransmitter type.     

Responding to daily event questionnaires: the influence of the order of hassle and uplift scales

Two studies demonstrated differences in hassle and uplift ratings of daily events as a function of questionnaire order and format. In the first study, 123 undergraduates rated 143 events as both sources of hassles and sources of uplifts. The order of completion of hassle and uplift ratings had a substantial impact on uplift ratings, but only a minor impact on hassle ratings. Events were rated less uplifting when these ratings followed rather than preceded hassle ratings. The second study replicated this asymmetric order effect for hassle and uplift ratings when events were restricted to the 53‐item Delongis scale and when a middle‐aged sample was used (n = 104). Furthermore, prior hassle ratings were shown to suppress uplift ratings not only when the two sets of ratings were separated, but also when the typical combined format of the Delongis scale was used. In this combined format, events are listed in a central column and one set of ratings (e.g. hassles) is completed on the left, the other set (e.g. uplifts) on the right. An additional result was that uplift ratings were higher for the combined format compared to the separated format. Results are discussed with reference to a possible effect of hassle recall/evaluation on negative mood, which may then impact on uplift recall/evaluation. The findings highlight the potentially differential impact of negative and positive events on individuals and provide a clear direction for the ordering of scales (i.e. positive before negative) in questionnaire packages. Copyright © 2002 John Wiley & Sons, Ltd.     

The ethics of psychopharmacological research in legal minors

Research in psychopharmacology for children and adolescents is fraught with ethical problems and tensions. This has practical consequences as it leads to a paucity of the research that is essential to support the treatment of this vulnerable group. In this article, we will discuss some of the ethical issues which are relevant to such research, and explore their implications for both research and standard care. We suggest that finding a way forward requires a willingness to acknowledge and discuss the inherent conflicts between the ethical principles involved. Furthermore, in order to facilitate more, ethically sound psychopharmacology research in children and adolescents, we suggest more ethical analysis, empirical ethics research and ethics input built into psychopharmacological research design.