Views of admitted palliative care patients and their clinicians on corneal donation discussions: a qualitative content analysis of semi-structured interviews.

BACKGROUND: There is a severe shortage of corneas for donation, globally, for transplantation and research purposes. One group of individuals who could potentially be donors are those who die within the inpatient palliative care unit. The aim of the study was to understand clinician and patient perceptions of corneal donations and discussion of donation in palliative care units. METHODS: A qualitative design was utilised with data collected through semi-structured interviews and analysed using qualitative content analysis. A total of 46 interviews were undertaken involving inpatient palliative care unit patients (19) and clinicians (27) in three major inpatient palliative care units in South Australia. RESULTS: Very few patient participants reported being asked about corneal donations during their time in palliative care. Most inpatient palliative care unit clinicians did not raise the topic as they felt other areas of care took precedence. Inpatient palliative care unit patients thought if inpatient palliative care unit clinicians did not raise the topic, then it was not important. There were some differences between patient and clinician views, such as preference about who raises the possibility of donation and when the discussion might occur. CONCLUSIONS: Findings suggest that patients are receptive to discussing corneal donations, but clinicians are not initiating these. This is a missed opportunity for donors and potential recipients. We recommend that clinicians routinely discuss eye donation as part of palliative care.

Survivorship Care for People Affected by Advanced or Metastatic Cancer: MASCC-ASCO Standards and Practice Recommendations.

PURPOSE: People with advanced or metastatic cancer and their caregivers may have different care goals and face unique challenges compared with those with early-stage disease or those nearing the end of life. These Multinational Association for Supportive Care in Cancer (MASCC)-ASCO standards and practice recommendations seek to establish consistent provision of quality survivorship care for people affected by advanced or metastatic cancer. METHODS: A MASCC-ASCO expert panel was formed. Standards and recommendations relevant to the provision of quality survivorship care for people affected by advanced or metastatic cancer were developed through conducting (1) a systematic review of unmet supportive care needs; (2) a scoping review of cancer survivorship, supportive care, and palliative care frameworks and guidelines; and (3) an international modified Delphi consensus process. RESULTS: A systematic review involving 81 studies and a scoping review of 17 guidelines and frameworks informed the initial standards and recommendations. Subsequently, 77 experts (including eight people with lived experience) across 33 countries (33% were low- to middle-resource countries) participated in the Delphi study and achieved ≥94.8% agreement for seven standards, (1) Person-Centered Care; (2) Coordinated and Integrated Care; (3) Evidence-Based and Comprehensive Care; (4) Evaluated and Communicated Care; (5) Accessible and Equitable Care; (6) Sustainable and Resourced Care; and (7) Research and Data-Driven Care, and ≥84.2% agreement across 45 practice recommendations. CONCLUSION: Standards of survivorship care for people affected by advanced or metastatic cancer are provided. These MASCC-ASCO standards support optimization of health outcomes and care experiences by providing guidance to stakeholders (health care professionals, leaders, and administrators; governments and health ministries; policymakers; advocacy agencies; cancer survivors and caregivers). Practice recommendations may be used to facilitate future research, practice, policy, and advocacy efforts.Additional information is available at www.mascc.org, www.asco.org/standards and www.asco.org/survivorship-guidelines.

Machine learning methods for predicting guide RNA effects in CRISPR epigenome editing experiments.

CRISPR epigenomic editing technologies enable functional interrogation of non-coding elements. However, current computational methods for guide RNA (gRNA) design do not effectively predict the power potential, molecular and cellular impact to optimize for efficient gRNAs, which are crucial for successful applications of these technologies. We present "launch-dCas9" (machine LeArning based UNified CompreHensive framework for CRISPR-dCas9) to predict gRNA impact from multiple perspectives, including cell fitness, wildtype abundance (gauging power potential), and gene expression in single cells. Our launchdCas9, built and evaluated using experiments involving >1 million gRNAs targeted across the human genome, demonstrates relatively high prediction accuracy (AUC up to 0.81) and generalizes across cell lines. Method-prioritized top gRNA(s) are 4.6-fold more likely to exert effects, compared to other gRNAs in the same cis-regulatory region. Furthermore, launchdCas9 identifies the most critical sequence-related features and functional annotations from >40 features considered. Our results establish launch-dCas9 as a promising approach to design gRNAs for CRISPR epigenomic experiments.

Survivorship care for people affected by advanced or metastatic cancer: MASCC-ASCO standards and practice recommendations.

PURPOSE: People with advanced or metastatic cancer and their caregivers may have different care goals and face unique challenges compared to those with early-stage disease or those nearing the end-of-life. These MASCC-ASCO standards and practice recommendations seek to establish consistent provision of quality survivorship care for people affected by advanced or metastatic cancer. METHODS: An expert panel comprising MASCC and ASCO members was formed. Standards and recommendations relevant to the provision of quality survivorship care for people affected by advanced or metastatic cancer were developed through conducting: (1) a systematic review of unmet supportive care needs; (2) a scoping review of cancer survivorship, supportive care, and palliative care frameworks and guidelines; and (3) an international modified Delphi consensus process. RESULTS: A systematic review involving 81 studies and a scoping review of 17 guidelines and frameworks informed the initial standards and recommendations. Subsequently, 77 experts (including 8 people with lived experience) across 33 countries (33% were low-to-middle resource countries) participated in the Delphi study and achieved ≥ 94.8% agreement for seven standards (1. Person-Centred Care; 2. Coordinated and Integrated Care; 3. Evidence-Based and Comprehensive Care; 4. Evaluated and Communicated Care; 5. Accessible and Equitable Care; 6. Sustainable and Resourced Care; 7. Research and Data-Driven Care) and ≥ 84.2% agreement across 45 practice recommendations. CONCLUSION: Standards of survivorship care for people affected by advanced or metastatic cancer are provided. These MASCC-ASCO standards will support optimization of health outcomes and care experiences by providing guidance to stakeholders in cancer care (healthcare professionals, leaders, and administrators; governments and health ministries; policymakers; advocacy agencies; cancer survivors and caregivers. Practice recommendations may be used to facilitate future research, practice, policy, and advocacy efforts.

Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/guidance on the use of clinically assisted hydration in patients with advanced cancer.

PURPOSE: The provision of clinically assisted hydration (CAH) in patients with advanced cancer is controversial, and there is a paucity of specific guidance and so a diversity in clinical practice. Consequently, the Palliative Care Study Group of the Multinational Association of Supportive Care in Cancer (MASCC) formed a sub-group to develop evidence-based guidance on the use of CAH in patients with advanced cancer. METHODS: This guidance was developed in accordance with the MASCC Guidelines Policy. A search strategy for Medline was developed, and the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were explored for relevant reviews/trials, respectively. RESULTS: Due to the paucity of evidence, the sub-group was not able to develop a prescribed guideline, but was able to generate a number of "expert opinion statements": these statements relate to assessment of patients, indications for CAH, contraindications for CAH, procedures for initiating CAH, and reassessment of patients. CONCLUSIONS: This guidance provides a framework for the use of CAH in advanced cancer, although every patient requires individualised management.

Subcutaneous sodium valproate in palliative care: A systematic review.

BACKGROUND: Seizures are an important palliative symptom, the management of which can be complicated by patients' capacity to swallow oral medications. In this setting, and the wish to avoid intravenous access, subcutaneous infusions may be employed. Options for antiseizure medications that can be provided subcutaneously may be limited. Subcutaneous sodium valproate may be an additional management strategy. AIM: To evaluate the published experience of subcutaneous valproate use in palliative care, namely with respect to effectiveness and tolerability. DESIGN: A systematic review was registered (PROSPERO CRD42023453427), conducted and reported according to PRISMA reporting guidelines. DATA SOURCES: The databases PubMed, EMBASE and Scopus were searched for publications until August 11, 2023. RESULTS: The searches returned 429 results, of which six fulfilled inclusion criteria. Case series were the most common study design, and most studies included <10 individuals who received subcutaneous sodium valproate. There were three studies that presented results on the utility of subcutaneous sodium valproate for seizure control, which described it to be an effective strategy. One study also described it as an effective treatment for neuropathic pain. The doses were often based on presumed 1:1 oral to subcutaneous conversion ratios. Only one study described a local site adverse reaction, which resolved with a change of administration site. CONCLUSIONS: There are limited data on the use of subcutaneous sodium valproate in palliative care. However, palliative symptoms for which subcutaneous sodium valproate have been used successfully are seizures and neuropathic pain. The available data have described few adverse effects, supporting its use with an appropriate degree of caution.

Personalised virtual reality in palliative care: clinically meaningful symptom improvement for some.

OBJECTIVES: This study examined the effects of virtual reality (VR) among palliative care patients at an acute ward. Objectives included evaluating VR therapy benefits across three sessions, assessing its differential impact on emotional versus physical symptoms and determining the proportion of patients experiencing clinically meaningful improvements after each session. METHODS: A mixed-methods design was employed. Sixteen palliative inpatients completed three personalised 20 min VR sessions. Symptom burden was assessed using the Edmonton Symptom Assessment Scale-Revised and quality of life with the Functional Assessment of Chronic Illness Therapy (FACIT-Pal-14). Standardised criteria assessed clinically meaningful changes. Quantitative data were analysed using linear mixed models. RESULTS: Quality of life improved significantly pre-VR to post-VR with a large effect size (Cohen's d: 0.98). Total symptom burden decreased after 20 min VR sessions (Cohen's d: 0.75), with similar effect sizes for emotional (Cohen's d: 0.67) and physical symptoms (Cohen's d: 0.63). Over 50% of patients experienced clinically meaningful improvements per session, though substantial individual variability occurred. CONCLUSIONS: This study reveals the nuanced efficacy of personalised VR therapy in palliative care, with over half of the patients experiencing meaningful benefits in emotional and physical symptoms. The marked variability in responses underscores the need for realistic expectations when implementing VR therapy.

Chromatin Remodeling in Patient-Derived Colorectal Cancer Models.

Patient-Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient-derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, the transcriptomic and chromatin accessibility landscapes of matched colorectal cancer (CRC) PDO, PDX, PDO-derived PDX (PDOX), and original patient tumors (PT) are compared. Two major remodeling axes are discovered. The first axis delineates PDMC from PT, and the second axis distinguishes PDX and PDO. PDOX are more similar to PDX than PDO, indicating the growth environment is a driving force for chromatin adaptation. Transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX are identified. Among them, KLF14 and EGR2 footprints are enriched in PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient-derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome.

Characterization of enhancer activity in early human neurodevelopment using Massively Parallel Reporter Assay (MPRA) and forebrain organoids.

Regulation of gene expression through enhancers is one of the major processes shaping the structure and function of the human brain during development. High-throughput assays have predicted thousands of enhancers involved in neurodevelopment, and confirming their activity through orthogonal functional assays is crucial. Here, we utilized Massively Parallel Reporter Assays (MPRAs) in stem cells and forebrain organoids to evaluate the activity of ~ 7000 gene-linked enhancers previously identified in human fetal tissues and brain organoids. We used a Gaussian mixture model to evaluate the contribution of background noise in the measured activity signal to confirm the activity of ~ 35% of the tested enhancers, with most showing temporal-specific activity, suggesting their evolving role in neurodevelopment. The temporal specificity was further supported by the correlation of activity with gene expression. Our findings provide a valuable gene regulatory resource to the scientific community.

Should Cannabis be Used for Anorexia in Patients With Cancer?

Healthcare professionals are frequently asked about the benefits of cannabis for appetite or anorexia-cachexia syndrome. In popular culture, cannabis has a reputation of causing an increased hunger, slang termed "the munchies," so many patients consume this with the hope that it may improve the loss of appetite associated with serious illness such as cancer. There have only been a few randomized, controlled trials studying the controversial question as to if cannabis improves appetite. These studies are small and show no statistically significant benefit for appetite and one small study showed improvement of taste for foods. Due to regulation barriers, the studies have use synthetic products, not the products that represent what is more commonly used in the population, often whole flower smoked, vaporized or oral products. Despite the popularity of cannabis in culture, often touted as a panacea for all maladies, the evidence and education for several adverse effects and potential drug interactions have has yet to catch up with the cultural craze. International cannabis experts in the United States and Australia do not routinely certify patients for medical cannabis off trial for anorexia-cachexia, but one expert in Canada would consider use in selected cancer patients.

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.

Epigenetic control of cellular transcription and phenotype is influenced by changes in the cellular microenvironment, yet how mechanical cues from these microenvironments precisely influence epigenetic state to regulate transcription remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a new class of genomic enhancers that responds to the mechanical microenvironment. These 'mechanoenhancers' could be active on either soft or stiff extracellular matrix contexts, and regulated transcription to influence critical cell functions including apoptosis, mechanotransduction, proliferation, and migration. Epigenetic editing of mechanoenhancers on rigid materials tuned gene expression to levels observed on softer materials, thereby reprogramming the cellular response to the mechanical microenvironment. These editing approaches may enable the precise alteration of mechanically-driven disease states.

Epstein-Barr virus induces germinal center light zone chromatin architecture and promotes survival through enhancer looping at the BCL2A1 locus.

IMPORTANCE: Epstein-Barr virus has evolved with its human host leading to an intimate relationship where infection of antibody-producing B cells mimics the process by which these cells normally recognize foreign antigens and become activated. Virtually everyone in the world is infected by adulthood and controls this virus pushing it into life-long latency. However, immune-suppressed individuals are at high risk for EBV+ cancers. Here, we isolated B cells from tonsils and compare the underlying molecular genetic differences between these cells and those infected with EBV. We find similar regulatory mechanism for expression of an important cellular protein that enables B cells to survive in lymphoid tissue. These findings link an underlying relationship at the molecular level between EBV-infected B cells in vitro with normally activated B cells in vivo. Our studies also characterize the role of a key viral control mechanism for B cell survival involved in long-term infection.

Supporting gut health with medicinal cannabis in people with advanced cancer: potential benefits and challenges.

The side effects of cancer therapy continue to cause significant health and cost burden to the patient, their friends and family, and governments. A major barrier in the way in which these side effects are managed is the highly siloed mentality that results in a fragmented approach to symptom control. Increasingly, it is appreciated that many symptoms are manifestations of common underlying pathobiology, with changes in the gastrointestinal environment a key driver for many symptom sequelae. Breakdown of the mucosal barrier (mucositis) is a common and early side effect of many anti-cancer agents, known to contribute (in part) to a range of highly burdensome symptoms such as diarrhoea, nausea, vomiting, infection, malnutrition, fatigue, depression, and insomnia. Here, we outline a rationale for how, based on its already documented effects on the gastrointestinal microenvironment, medicinal cannabis could be used to control mucositis and prevent the constellation of symptoms with which it is associated. We will provide a brief update on the current state of evidence on medicinal cannabis in cancer care and outline the potential benefits (and challenges) of using medicinal cannabis during active cancer therapy.

Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains.

BACKGROUND: The genetic underpinnings of late-onset Alzheimer's disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD. METHODS: Here, we present the largest parallel single-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co-accessibility networks (CCANs). RESULTS: Integrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype-specific candidate cis regulatory elements (cCREs), their candidate target genes, and trans-interacting transcription factors (TFs), some of which, including ELK1, JUN, and SMAD4 in excitatory neurons, were also LOAD-DEGs. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs, including APOE and MYO1E in a specific subtype of microglia and BIN1 in a subpopulation of oligodendrocytes. CONCLUSIONS: To our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings reveal crosstalk between epigenetic, genomic, and transcriptomic determinants of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specific cis-trans interactions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.

Characterization of enhancer activity in early human neurodevelopment using Massively parallel reporter assay (MPRA) and forebrain organoids.

Regulation of gene expression through enhancers is one of the major processes shaping the structure and function of the human brain during development. High-throughput assays have predicted thousands of enhancers involved in neurodevelopment, and confirming their activity through orthogonal functional assays is crucial. Here, we utilized Massively Parallel Reporter Assays (MPRAs) in stem cells and forebrain organoids to evaluate the activity of ~7,000 gene-linked enhancers previously identified in human fetal tissues and brain organoids. We used a Gaussian mixture model to evaluate the contribution of background noise in the measured activity signal to confirm the activity of ~35% of the tested enhancers, with most showing temporal-specific activity, suggesting their evolving role in neurodevelopment. The temporal specificity was further supported by the correlation of activity with gene expression. Our findings provide a valuable gene regulatory resource to the scientific community.

Psychological service provision in Australian Palliative Care Services.

OBJECTIVES: Psychological distress is common among palliative care patients. Despite this, little is known about the availability of psychological services to support palliative care patients within Australia. This study aimed to determine the level of psychological support services available within Australian Palliative Care Services. The study was based on a similar study in Australia by Crawford in 1999, allowing differences over time to be examined. METHODS: A 12-item online survey was distributed to adult Palliative Care Services throughout Australia from November 2021 to January 2022. Quantitative and qualitative analysis of responses was conducted, with comparisons made with the 1999 study using a 2-proportions z-test. RESULTS: Social workers were the most available professionals delivering psychological care (prevalence of 94.1%), followed by spiritual care workers (62.5%), creative therapists (43.8%), counselors (36.4%), psychiatrists (31.3%), complementary therapists (28.1%), and psychologists (25.0%). Nearly 60% of services had no access to a psychiatrist or a psychologist. The proportion of Palliative Care Services that had access to a psychiatrist, psychologist, or counselor was significantly less in 2021/22 compared to 1999, with differences of 29.4% (p = 0.002), 23.4% (p = 0.015), and 26.1% (p = 0.006), respectively. SIGNIFICANCE OF RESULTS: Lack of access to psychiatrists, psychologists, and counselors in Australian Palliative Care Services remains a significant issue and has become more prevalent since 1999. Ongoing advocacy and increased government funding to enable psychological health professionals to be readily employed in Palliative Care Services is vital.

An evidence-base for the implementation of hospital-based palliative care programs in routine cancer practice: A systematic review.

BACKGROUND: Despite global support, there remain gaps in the integration of early palliative care into cancer care. The methods of implementation whereby evidence of benefits of palliative care is translated into practice deserve attention. AIM: To identify implementation frameworks utilised in integrated palliative care in hospital-based oncology services and to describe the associated enablers and barriers to service integration. DESIGN: Systematic review with a narrative synthesis including qualitative, mixed methods, pre-post and quasi experimental designs following the guidance by the Centre for Reviews and Dissemination (PROSPERO registration CRD42021252092). DATA SOURCES: Six databases searched in 2021: EMBASE, EMCARE, APA PsycINFO, CINAHL, Cochrane Library and Ovid MEDLINE searched in 2023. Included were qualitative or quantitative studies, in English language, involving adults >18 years, and implementing hospital-based palliative care into cancer care. Critical appraisal tools were used to assess the quality and rigour. RESULTS: Seven of the 16 studies explicitly cited the use of frameworks including those based on RE-AIM, Medical Research Council evaluation of complex interventions and WHO constructs of health service evaluation. Enablers included an existing supportive culture, clear introduction to the programme across services, adequate funding, human resources and identification of advocates. Barriers included a lack of communication with the patients, caregivers, physicians and palliative care team about programme goals, stigma around the term 'palliative', a lack of robust training, or awareness of guidelines and undefined staff roles. CONCLUSIONS: Implementation science frameworks provide a method to underpin programme development and evaluation as palliative care is integrated within the oncology setting.