'He just gave up': an exploratory study into the perspectives of paid carers on supporting older people living in care homes with depression, self-harm, and suicide ideation and behaviours

This study explored the concept of ‘giving up’ from the perspective of care staff working in care homes, and their everyday communication and hidden knowledge concerning what they think about this taboo topic and the context it reflects. Moving to a care home is a major transition where cumulative losses can pose risks to mental health in later life. If not recognised, this vulnerability can lead to depression which extends to suicide ideation and behaviours in the form of self-harm and self-neglect. Care homes are a significant place of care until death, yet a discourse of silence means that self-harm and suicide is under-reported or not attended to with specialist expertise. The layperson’s concept of an older person ‘giving up’ on life is hardly discussed in the literature. This co-produced qualitative study used an inductive approach to explore this phenomenon through focus groups with 33 care staff across four care homes in South-East England. Findings paint a complex picture, highlighting tensions in providing the right support and creating spaces to respond to such challenging situations. ‘Giving up’ requires skilled detailed assessment to respond to risks alongside improved training and support for paid carers, to achieve a more holistic strategy which capitalises on significant relationships within a wider context

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'He just gave up': an exploratory study into the perspectives of paid carers on supporting older people living in care homes with depression, self-harm, and suicide ideation and behaviours

This study explored the concept of ‘giving up’ from the perspective of care staff working in care homes, and their everyday communication and hidden knowledge concerning what they think about this taboo topic and the context it reflects. Moving to a care home is a major transition where cumulative losses can pose risks to mental health in later life. If not recognised, this vulnerability can lead to depression which extends to suicide ideation and behaviours in the form of self-harm and self-neglect. Care homes are a significant place of care until death, yet a discourse of silence means that self-harm and suicide is under-reported or not attended to with specialist expertise. The layperson’s concept of an older person ‘giving up’ on life is hardly discussed in the literature. This co-produced qualitative study used an inductive approach to explore this phenomenon through focus groups with 33 care staff across four care homes in South-East England. Findings paint a complex picture, highlighting tensions in providing the right support and creating spaces to respond to such challenging situations. ‘Giving up’ requires skilled detailed assessment to respond to risks alongside improved training and support for paid carers, to achieve a more holistic strategy which capitalises on significant relationships within a wider context

A functional siRNA screen identifies genes modulating angiotensin II-mediated EGFR transactivation

The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, however, the molecular mechanisms involved have not yet been resolved. To address this, we performed a functional siRNA screen of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R-EGFR transactivation. We identified a suite of genes encoding proteins that both positively and negatively regulate AT1R-EGFR transactivation. Many candidates are components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, have not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but this did not occur following direct stimulation of the EGFR with EGF, indicating that these proteins function between the activated AT1R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT1R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another G protein-coupled receptor (GPCR) ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for tissue remodelling in cardiovascular disease and cancer.This work was supported by the Australian National Health and Medical Research Council project grants [grant numbers 472640, 1024726 to W.G.T. and R.D.H]; and a project grant awarded to R.D.H, funded in Australia by the Captain Courageous Foundation (http://www.captaincourageousfoundation.com). R.D.H also holds an NHMRC senior research fellowship [grant number 1022402]

Multicellular transcriptional analysis of mammalian heart regeneration

BACKGROUND: The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time. METHODS: Cardiomyocytes, fibroblasts, leukocytes, and endothelial cells from infarcted and noninfarcted neonatal (P1) and adult (P56) mouse hearts were isolated by enzymatic dissociation and fluorescence-activated cell sorting at day 3 following surgery. RNA sequencing was performed on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair, and regeneration. To complement our transcriptomic data, we also surveyed the epigenetic landscape of cardiomyocytes during postnatal maturation by performing deep sequencing of accessible chromatin regions by using the Assay for Transposase-Accessible Chromatin from purified mouse cardiomyocyte nuclei (P1, P14, and P56). RESULTS: Profiling of cardiomyocyte and nonmyocyte transcriptional programs uncovered several injury-responsive genes across regenerative and nonregenerative time points. However, the majority of transcriptional changes in all cardiac cell types resulted from developmental maturation from neonatal stages to adulthood rather than activation of a distinct regeneration-specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state. In contrast, cardiomyocytes failed to reactivate the neonatal proliferative network following infarction, which was associated with loss of chromatin accessibility around cell cycle genes during postnatal maturation. CONCLUSIONS: This work provides a comprehensive framework and transcriptional resource of multiple cardiac cell populations during cardiac development, repair, and regeneration. Our findings define a regulatory program underpinning the neonatal regenerative state and identify alterations in the chromatin landscape that could limit reinduction of the regenerative program in adult cardiomyocytes

Mechanisms and Therapeutic Targets of Cardiac Regeneration: Closing the Age Gap

While a regenerative response is limited in the mammalian adult heart, it has been recently shown that the neonatal mammalian heart possesses a marked but transient capacity for regeneration after cardiac injury, including myocardial infarction. These findings evidence that the mammalian heart still retains a regenerative capacity and highlights the concept that the expression of distinct molecular switches (that activate or inhibit cellular mechanisms regulating tissue development and regeneration) vary during different stages of life, indicating that cardiac regeneration is an age-dependent process. Thus, understanding the mechanisms underpinning regeneration in the neonatal-infarcted heart is crucial to develop new treatments aimed at improving cardiovascular regeneration in the adult. The present review summarizes the current knowledge on the pathways and factors that are known to determine cardiac regeneration in the neonatal-infarcted heart. In particular, we will focus on the effects of microRNA manipulation in regulating cardiomyocyte proliferation and regeneration, as well as on the role of the Hippo signaling pathway and Meis1 in the regenerative response of the neonatal-infarcted heart. We will also briefly comment on the role of macrophages in scar formation of the adult-infarcted heart or their contribution for scar-free regeneration of the neonatal mouse heart after myocardial infarction. Although additional research is needed in order to identify other factors that regulate cardiovascular regeneration, these pathways represent potential therapeutic targets for rejuvenation of aging hearts and for improving regeneration of the adult-infarcted heart

Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity

Abstract: It is unclear why some tissues are refractory to the mitogenic effects of the oncogene Myc. Here we show that Myc activation induces rapid transcriptional responses followed by proliferation in some, but not all, organs. Despite such disparities in proliferative response, Myc is bound to DNA at open elements in responsive (liver) and non-responsive (heart) tissues, but fails to induce a robust transcriptional and proliferative response in the heart. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription is re-engaged in mature cardiomyocytes by elevating levels of the positive transcription elongation factor (P-TEFb), instating a large proliferative response. Hence, P-TEFb activity is a key limiting determinant of whether the heart is permissive for Myc transcriptional activation. These data provide a greater understanding of how Myc transcriptional activity is determined and indicate modification of P-TEFb levels could be utilised to drive regeneration of adult cardiomyocytes for the treatment of heart myopathies

The effect of LRRK2 loss-of-function variants in humans

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery. Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes(1,2). Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease(3,4), suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns(5-8), the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)(9), 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work(10), confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.Peer reviewe

Determinants of woody encroachment and cover in African savannas

Savanna ecosystems are an integral part of the African landscape and sustain the livelihoods of millions of people. Woody encroachment in savannas is a widespread phenomenon but its causes are widely debated. We review the extensive literature on woody encroachment to help improve understanding of the possible causes and to highlight where and how future scientific efforts to fully understand these causes should be focused. Rainfall is the most important determinant of maximum woody cover across Africa, but fire and herbivory interact to reduce woody cover below the maximum at many locations. We postulate that woody encroachment is most likely driven by CO2 enrichment and propose a two-system conceptual framework, whereby mechanisms of woody encroachment differ depending on whether the savanna is a wet or dry system. In dry savannas, the increased water-use efficiency in plants relaxes precipitation-driven constraints and increases woody growth. In wet savannas, the increase of carbon allocation to tree roots results in faster recovery rates after disturbance and a greater likelihood of reaching sexual maturity. Our proposed framework can be tested using a mixture of experimental and earth observational techniques. At a local level, changes in precipitation, burning regimes or herbivory could be driving woody encroachment, but are unlikely to be the explanation of this continent-wide phenomenon

Importance of patient bed pathways and length of stay differences in predicting COVID-19 hospital bed occupancy in England.

Background: Predicting bed occupancy for hospitalised patients with COVID-19 requires understanding of length of stay (LoS) in particular bed types. LoS can vary depending on the patient’s “bed pathway” - the sequence of transfers of individual patients between bed types during a hospital stay. In this study, we characterise these pathways, and their impact on predicted hospital bed occupancy. Methods: We obtained data from University College Hospital (UCH) and the ISARIC4C COVID-19 Clinical Information Network (CO-CIN) on hospitalised patients with COVID-19 who required care in general ward or critical care (CC) beds to determine possible bed pathways and LoS. We developed a discrete-time model to examine the implications of using either bed pathways or only average LoS by bed type to forecast bed occupancy. We compared model-predicted bed occupancy to publicly available bed occupancy data on COVID-19 in England between March and August 2020. Results: In both the UCH and CO-CIN datasets, 82% of hospitalised patients with COVID-19 only received care in general ward beds. We identified four other bed pathways, present in both datasets: “Ward, CC, Ward”, “Ward, CC”, “CC” and “CC, Ward”. Mean LoS varied by bed type, pathway, and dataset, between 1.78 and 13.53 days. For UCH, we found that using bed pathways improved the accuracy of bed occupancy predictions, while only using an average LoS for each bed type underestimated true bed occupancy. However, using the CO-CIN LoS dataset we were not able to replicate past data on bed occupancy in England, suggesting regional LoS heterogeneities. Conclusions: We identified five bed pathways, with substantial variation in LoS by bed type, pathway, and geography. This might be caused by local differences in patient characteristics, clinical care strategies, or resource availability, and suggests that national LoS averages may not be appropriate for local forecasts of bed occupancy for COVID-19. Trial registration: The ISARIC WHO CCP-UK study ISRCTN66726260 was retrospectively registered on 21/04/2020 and designated an Urgent Public Health Research Study by NIHR.</p