Living with Parkinson's in England during and beyond COVID-19 restrictions: a longitudinal qualitative study.

OBJECTIVES: Government-enforced lockdown restrictions associated with preventing the spread of the COVID-19 virus had a series of unintended, negative effects. One group of individuals whose physical and mental health was significantly and disproportionately impacted were those with Parkinson's. However, research has been mainly cross-sectional, with no previous study qualitatively following up participants through both lockdowns and the easing of restrictions. Consequently, this study aimed to provide a detailed understanding of the experience of lockdowns and the easing of restrictions on the physical and mental health of people with Parkinson's. METHOD: Data from semi-structured interviews collected at four time points across an 18-month period (May 2020 - September 2021) from the same participants (six men and four women) were analysed using interpretative phenomenological analysis. RESULTS: Three themes were derived: (1) Wrestling with a Parkinson's identity, agency and control during the pandemic; (2) The encroachment and acceleration of a Parkinson's future; and (3) Recalibrating priorities from COVID-19 to Parkinson's. CONCLUSION: As currently the only published study to provide an in-depth longitudinal analysis with this population, we used a more dynamic theoretical account, Strauss and Corbin's theory of illness trajectories, to understand the findings and suggest ways of supporting individuals with Parkinson's in this stage of the pandemic. The scale and breadth of the support needed is a significant challenge for current statutory systems.

Understanding the impact of the Covid-19 pandemic on delivery of rehabilitation in specialist palliative care services: An analysis of the CovPall-Rehab survey data.

BACKGROUND: Palliative rehabilitation involves multi-professional processes and interventions aimed at optimising patients' symptom self-management, independence and social participation throughout advanced illness. Rehabilitation services were highly disrupted during the Covid-19 pandemic. AIM: To understand rehabilitation provision in palliative care services during the Covid-19 pandemic, identifying and reflecting on adaptative and innovative practice to inform ongoing provision. DESIGN: Cross-sectional national online survey. SETTING/PARTICIPANTS: Rehabilitation leads for specialist palliative care services across hospice, hospital, or community settings, conducted from 30/07/20 to 21/09/2020. FINDINGS: 61 completed responses (England, n = 55; Scotland, n = 4; Wales, n = 1; and Northern Ireland, n = 1) most frequently from services based in hospices (56/61, 92%) providing adult rehabilitation. Most services (55/61, 90%) reported rehabilitation provision becoming remote during Covid-19 and half reported reduced caseloads. Rehabilitation teams frequently had staff members on sick-leave with suspected/confirmed Covid-19 (27/61, 44%), redeployed to other services/organisations (25/61, 41%) or furloughed (15/61, 26%). Free text responses were constructed into four themes: (i) fluctuating shared spaces; (ii) remote and digitised rehabilitation offer; (iii) capacity to provide and participate in rehabilitation; (iv) Covid-19 as a springboard for positive change. These represent how rehabilitation services contracted, reconfigured, and were redirected to more remote modes of delivery, and how this affected the capacity of clinicians and patients to participate in rehabilitation. CONCLUSION: This study demonstrates how changes in provision of rehabilitation during the pandemic could act as a springboard for positive changes. Hybrid models of rehabilitation have the potential to expand the equity of access and reach of rehabilitation within specialist palliative care.

Charitably funded hospices and the challenges associated with the COVID-19 pandemic: a mixed-methods study (CovPall).

BACKGROUND: Independent charitably funded hospices have been an important element of the UK healthcare response to the COVID-19 pandemic. Hospices usually have different funding streams, procurement processes, and governance arrangements compared to NHS provision, which may affect their experiences during the COVID-19 pandemic. The aim of this study is to understand the challenges faced by charitably funded hospices during the COVID-19 pandemic. METHODS: Eligible Organisations providing specialist palliative or hospice care completed the online CovPall survey (2020) which explored their response to the COVID-19 pandemic. Eligible organisations were then purposively selected to participate in interviews as part of qualitative case studies (2020-21) to understand challenges in more depth. Free-text responses from the survey were analysed using content analysis and were categorised accordingly. These categorisations were used a priori for a reflexive thematic analysis of interview data. RESULTS: 143 UK independent charitably funded hospices completed the online CovPall survey. Five hospices subsequently participated in qualitative case studies (n = 24 staff interviews). Key themes include: vulnerabilities of funding; infection control during patient care; and bereavement support provision. Interviewees discussed the fragility of income due to fundraising events stopping; the difficulties of providing care to COVID-19 and non-COVID-19 patients within relatively small organisations; and challenges with maintaining the quality of bereavement services. CONCLUSION: Some unique care and provision challenges during the COVID-19 pandemic were highlighted by charitably funded hospices. Funding core services charitably and independently may affect their ability to respond to pandemics, or scenarios where resources are unexpectedly insufficient.

Age-friendliness of living environments from the older person's viewpoint: development of the Age-Friendly Environment Assessment Tool.

BACKGROUND: according to the World Health Organisation, the role of the environment for older adults is to maintain and facilitate independence and promote quality of life. However, measures that examine the environment in terms of its potential impact on older people are either oriented towards specific aspects of the environment, specifically designed for community-level assessment rather than individually oriented, or are unwieldy for everyday use. OBJECTIVES: this article describes the development and validation of the Age-Friendly Environment Assessment Tool (AFEAT), assessing whether individual function and frailty impact on perceptions of environmental age-friendliness. The extent to which such perceptions may have moderate impacts of frailty on outcomes such as need for care support, quality of life and loneliness is examined. METHODS: a total of 132 participants aged 58-96 were recruited from retirement villages and local communities in the Midlands of the UK. Participants completed the AFEAT, and a series of measures designed to assess frailty and assessments of quality of life, loneliness and perceptions of functional limitations. RESULTS: internal reliability assessment indicated that the AFEAT possesses a Cronbach's Alpha score of 0.745. The AFEAT significantly predicted quality of life and loneliness, accounting for 17.1% and 5.8% of variance respectively, indicating high concurrent and predictive validity. Furthermore, the AFEAT moderated the predictive strength of frailty in predicting the amount of formal care an individual receives, but not quality of life or loneliness. DISCUSSION: the AFEAT is a valid and reliable tool, and analyses highlight the need for an individual-oriented Age-Friendly environment tool.

Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis.

Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E2, due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE2 production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4.

The joint impact of symptom deterioration and social factors on wellbeing for people with Parkinson's during the covid-19 pandemic in the UK.

The covid-19 pandemic and associated restrictions have had significant consequences for those living with chronic conditions such as Parkinson's. The restrictions in access to healthcare as well as reductions in social care, family support and community activities have led to decreases in physical and mental wellbeing. However, not everyone has been equally affected and the predictors of distress are currently being investigated worldwide. Here we use data from a UK survey conducted by the charity Parkinson's UK during Summer 2021 to look at physical and social predictors of wellbeing of people with Parkinson's. Specifically, we aimed to look at the combined effects of worsening physical symptoms, social isolation and loneliness on psychological wellbeing when controlling for age, gender and disease duration. The data from 612 participants were analysed using multiple regression analyses and showed that worsened physical symptoms, loneliness and social isolation each independently predicted wellbeing thus showing the impact of both physical symptoms and social factors. Improved access to healthcare and physical activity is needed to help improve physical health. However, addressing the social needs of people with Parkinson's is also important, and not only during a pandemic. Additional interventions may be needed to reduce social isolation and loneliness as there may be added barriers for people with Parkinson's which need to be considered.

Is There a Role for Epigenetic Therapies in Modulating DNA Damage Repair Pathways to Enhance Chemotherapy and Overcome Drug Resistance?

Epigenetic therapies describe drug molecules such as DNA methyltransferase, histone methyltransferase and histone acetylase/deacetylase inhibitors, which target epigenetic mechanisms such as DNA methylation and histone modifications. Many DNA damage response (DDR) genes are epigenetically regulated in cancer leading to transcriptional silencing and the loss of DNA repair capacity. Epigenetic marks at DDR genes, such as DNA methylation at gene promoters, have the potential to be used as stratification biomarkers, identifying which patients may benefit from particular chemotherapy treatments. For genes such as MGMT and BRCA1, promoter DNA methylation is associated with chemosensitivity to alkylating agents and platinum coordination complexes, respectively, and they have use as biomarkers directing patient treatment options. In contrast to epigenetic change leading to chemosensitivity, DNA methylation of DDR genes involved in engaging cell death responses, such as MLH1, are associated with chemoresistance. This contrasting functional effect of epigenetic modification on chemosensitivity raises challenges in using DNA-demethylating agents, and other epigenetic approaches, to sensitise tumours to DNA-damaging chemotherapies and molecularly targeted agents. Demethylation of MGMT/BRCA1 could lead to drug resistance whereas demethylation of MLH1 could sensitise cells to chemotherapy. Patient selection based on a solid understanding of the disease pathway will be one means to tackle these challenges. The role of epigenetic modification of DDR genes during tumour development, such as causing a mutator phenotype, has different selective pressures and outcomes compared to epigenetic adaptation during treatment. The prevention of epigenetic adaptation during the acquisition of drug resistance will be a potential strategy to improve the treatment of patients using epigenetic therapies.

An observational cohort study of longitudinal impacts on frailty and well-being of COVID-19 lockdowns in older adults in England and Spain.

To reduce the spread of COVID-19, governments initiated lockdowns, limiting mobility and social interaction of populations. Lockdown is linked to health issues, yet the full impact on health remains unknown, particularly in more vulnerable groups. This study examined the impact on frailty and outcomes in high and low COVID-19 risk older adults. We examined health-related behaviours and support resources participants used during lockdown(s). Lockdown impacts in two countries were compared across four time points to examine impacts of different rules. We recruited 70 participants (aged >70 years) in England and Spain. Participants were allocated to higher or lower COVID-19-risk groups based on UK NHS guidelines. They completed assessments for frailty, quality-of-life, loneliness, exercise frequency and social interaction, coping resources and perception of age-friendliness of their environment. The four assessments took place over a 7-month period. Frailty was highest at Time 1 (most severe lockdown restrictions) and significantly higher in the Spanish group. It was lower at Time 3 (lowest restrictions), but did not continue to reduce for the English participants. Perceptions of the age friendliness of the environment matched these changes. Coping resources did not mitigate changes in frailty and outcomes over time, but more frequent physical activity predicted more reduction in frailty. Lockdown had a negative impact on frailty, increasing risk of adverse events for older people, but recovery once lockdowns are eased is evidenced. Further research is required to consider longer term impacts and methods to mitigate effects of lockdown on health.

Experiences of staff providing specialist palliative care during COVID-19: a multiple qualitative case study.

OBJECTIVE: To explore the experiences of, and impact on, staff working in palliative care during the COVID-19 pandemic. DESIGN: Qualitative multiple case study using semi-structured interviews between November 2020 and April 2021 as part of the CovPall study. Data were analysed using thematic framework analysis. SETTING: Organisations providing specialist palliative services in any setting. PARTICIPANTS: Staff working in specialist palliative care, purposefully sampled by the criteria of role, care setting and COVID-19 experience. MAIN OUTCOME MEASURES: Experiences of working in palliative care during the COVID-19 pandemic. RESULTS: Five cases and 24 participants were recruited (n = 12 nurses, 4 clinical managers, 4 doctors, 2 senior managers, 1 healthcare assistant, 1 allied healthcare professional). Central themes demonstrate how infection control constraints prohibited and diluted participants' ability to provide care that reflected their core values, resulting in experiences of moral distress. Despite organisational, team and individual support strategies, continually managing these constraints led to a 'crescendo effect' in which the impacts of moral distress accumulated over time, sometimes leading to burnout. Solidarity with colleagues and making a valued contribution provided 'moral comfort' for some. CONCLUSIONS: This study provides a unique insight into why and how healthcare staff have experienced moral distress during the pandemic, and how organisations have responded. Despite their experience of dealing with death and dying, the mental health and well-being of palliative care staff was affected by the pandemic. Organisational, structural and policy changes are urgently required to mitigate and manage these impacts.

Prohibit, Protect, or Adapt? The Changing Role of Volunteers in Palliative and Hospice Care Services During the COVID-19 Pandemic. A Multinational Survey (Covpall).

BACKGROUND: Volunteers are common within palliative care services, and provide support that enhances care quality. The support they provided, and any role changes, during the coronavirus disease 2019 (COVID-19) pandemic are unknown. The aim of this study is to understand volunteer deployment and activities within palliative care services, and to identify what may affect any changes in volunteer service provision, during the COVID-19 pandemic. METHODS: Multi-national online survey disseminated via key stakeholders to specialist palliative care services, completed by lead clinicians. Data collected on volunteer roles, deployment, and changes in volunteer engagement. Analysis included descriptive statistics, a multivariable logistic regression, and analysis of free-text comments using a content analysis approach. RESULTS: 458 respondents: 277 UK, 85 rest of Europe, and 95 rest of the world. 68.5% indicated volunteer use pre-COVID-19 across a number of roles (from 458): direct patient facing support (58.7%), indirect support (52.0%), back office (48.5%) and fundraising (45.6%). 11% had volunteers with COVID-19. Of those responding to a question on change in volunteer deployment (328 of 458) most (256/328, 78%) indicated less or much less use of volunteers. Less use of volunteers was associated with being an in-patient hospice, (odds ratio [OR]=0.15, 95% CI=0.07-0.3, P<.001). This reduction in volunteers was felt to protect potentially vulnerable volunteers, with policy changes preventing volunteer support. However, adapting was also seen where new roles were created, or existing roles pivoted to provide virtual support. CONCLUSION: Volunteers were mostly prevented from supporting many forms of palliative care which may have quality and safety implications given their previously central roles. Volunteer re-deployment plans are needed that take a more considered approach, using volunteers more flexibly to enhance care while ensuring safe working practices. Consideration needs to be given to widening the volunteer base away from those who may be considered to be most vulnerable to COVID-19.

Dual G9A/EZH2 Inhibition Stimulates Antitumor Immune Response in Ovarian High-Grade Serous Carcinoma.

Ovarian high-grade serous carcinoma (HGSC) prognosis correlates directly with presence of intratumoral lymphocytes. However, cancer immunotherapy has yet to achieve meaningful survival benefit in patients with HGSC. Epigenetic silencing of immunostimulatory genes is implicated in immune evasion in HGSC and re-expression of these genes could promote tumor immune clearance. We discovered that simultaneous inhibition of the histone methyltransferases G9A and EZH2 activates the CXCL10-CXCR3 axis and increases homing of intratumoral effector lymphocytes and natural killer cells while suppressing tumor-promoting FoxP3+ CD4 T cells. The dual G9A/EZH2 inhibitor HKMTI-1-005 induced chromatin changes that resulted in the transcriptional activation of immunostimulatory gene networks, including the re-expression of elements of the ERV-K endogenous retroviral family. Importantly, treatment with HKMTI-1-005 improved the survival of mice bearing Trp53-/- null ID8 ovarian tumors and resulted in tumor burden reduction. These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumor growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.

Impacts of COVID-19 lockdowns on frailty and wellbeing in older people and those living with long-term conditions.

Lockdowns and social distancing have been important and successful strategies to limit the spread of the coronavirus disease 2019 (COVID-19) virus. However, excess deaths related to non-COVID-19 causes have been reported, suggesting issues around availability and use of health services, particularly for people with conditions needing ongoing medical support. In addition, evidence indicates that a range of age-related diseases and frailty are impacted by physical activity and social engagement, both limited in lockdown situations. It is therefore important to learn from the effects of lockdowns in order to limit any impacts, while still protecting people from the infection. This editorial summarizes two research themes at the Centre for Ageing Research at Lancaster University in the UK, one assessing impacts of lockdown for people living with a long-term neurodegenerative condition, Parkinson's disease, and one assessing longitudinal impacts on frailty and wellbeing, with older adults aged over 70, including those living with at least one long-term condition. Uncertainty related to Parkinson's disease and to COVID-19 amplified each other, and cancelled clinical appointments and limitations on physical activity had very significant impacts on wellbeing for this group. In the longitudinal study, frailty was more severe during lockdown periods. While lockdowns reduce spread of the virus, becoming frailer could make older adults more vulnerable to the effects of the virus during these periods. Regular exercise during lockdown had beneficial effects aiding recovery once restrictions relaxed. These studies suggest factors that could lessen negative impacts of future lockdowns. Maintaining physical activity and providing access to health services during periods of lockdown are suggested as priorities.

Chromatin accessibility changes at intergenic regions are associated with ovarian cancer drug resistance.

BACKGROUND: Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy. RESULTS: Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. CONCLUSIONS: Chromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.

Animation or leaflet: Does it make a difference when educating young people about genome sequencing?

OBJECTIVE: To compare the effectiveness of an animation against two leaflets with and without images, in educating young people about genome sequencing (GS). METHODS: An experimental survey with three assessment points (pre- intervention [T1], post - intervention [T2], 6-week follow-up [T3]). Participants (N = 606) were randomly assigned to receive one of three educational interventions; animation (n = 212); leaflet with images (n = 197); or leaflet with text only (n = 197). Measures of objective and subjective knowledge were completed at T1 (N = 606), T2 (N = 606) and T3 (N = 459). Measures of attitudes, intentions and beliefs towards GS and satisfaction with intervention were completed at T2 only. RESULTS: The type of educational intervention young people received had no significant impact on their objective or subjective knowledge at both T2 and T3 (all p > .05), nor did the educational intervention type affect their attitudes, intentions and beliefs towards GS at T2 (p > .05). However, participant satisfaction was significantly higher in the animation group than the leaflet groups (p < .001). CONCLUSION: Animations and leaflets are both effective ways to deliver genomic education to young people, but the animations lead to higher satisfaction. PRACTICE IMPLICATIONS: Different individuals may find different modes of educational resources more accessible than others. Therefore a range of resources should ideally be made available to patients.

Developing and validating the Community-Oriented Frailty Index (COM-FI).

INTRODUCTION: Methods for measuring frailty over-emphasise physical health, and consensus for a more holistic approach is increasing. However, holistic tools have had mixed success in meeting the validation criteria required of a frailty index. We report on the further development and validation of a Frailty Tool designed for use in the community with a greater emphasis on psychological markers, Holland et al's Community-Oriented Frailty Index (COM-FI). METHOD: A total of 351 participants aged 58-96 were recruited from Retirement Villages and local communities across the West Midlands of the UK. Participants completed a series of measures designed to assess frailty and outcomes associated with frailty over a 2-year period. RESULTS: All three candidate items ('polypharmacy', 'exercise frequency', and the Coronary Heart Disease and Diabetes 'joint effect') were incorporated into the tool, and one variable, 'falls' was removed from the index. The revised COM-FI was shown to be valid and met Rockwood's validation criteria (Rockwood et al., 2006), with the exception that in this specific sample there was no significant gender difference and the index did not predict mortality. DISCUSSION: Overall, the COM-FI is a valid and reliable tool, although the capacity for the COM-FI to predict mortality over a 2-year period remains inconclusive given the small numbers of people at the higher ends of the frailty range. Prediction of need for social care was good, showing the utility of this community based tool.

Using Chromatin Accessibility to Delineate Therapeutic Subtypes in Pancreatic Cancer Patient-Derived Cell Lines.

Disrupted chromatin regulatory processes contribute to the development of cancer, in particular pancreatic ductal adenocarcinoma. The assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) is typically used to study chromatin organization. Here, we present a revised ATAC-seq protocol to study chromatin accessibility in adherent patient-derived cell lines. We provide details on how to calculate the library molarity using Agilent's Bioanalyzer and an analysis pipeline for peak calling and transcription factor mapping. For complete details on the use and execution of this protocol, please refer to Brunton et al. (2020).

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3ß) a key regulator of glycolysis. Pharmacological inhibition of GSK3ß results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3ß inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.