COVID‐19: Impact on children living in out‐of‐home care and their carers

Children enter out‐of‐home care (OOHC) having experienced significant childhood adversities and trauma. Little is known about the short‐term impacts of the COVID‐19 pandemic on this vulnerable group. To gain some insights, we analysed the early impacts on the well‐being and experiences of children in OOHC and their carers using the Pathways of Care Longitudinal Study data prior to and post the first lockdown restrictions. A total of 862 children, young people and their carers were interviewed either pre‐COVID‐19 restrictions (n = 567) (April 2019–March 2020) or post‐COVID‐19 restrictions (n = 295) (June–December 2020). While the two groups showed no significant differences in socio‐emotional well‐being, both the pre‐ and the post‐COVID‐19 restriction groups of children in OOHC had slight reductions in socio‐emotional well‐being. The interviews with the post‐COVID‐19 group showed that the pandemic restrictions affected children's well‐being and behaviour, education, social and physical activities, as well as time spent with their birth family. Likewise, interviews with carers post‐COVID‐19 found a negative effect on carers' well‐being, their ability to manage financially and their capacity to care and access services and support. The article contributes new evidence to inform OOHC policy and practice to support service systems facing unique challenges arising from a pandemic. [ABSTRACT FROM AUTHOR] Copyright of Australian Journal of Social Issues (John Wiley & Sons, Inc. ) is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Dual mechanism: Epigenetic inhibitor apabetalone reduces SARS-CoV-2 Delta and Omicron variant spike binding and attenuates SARS-CoV-2 RNA induced inflammation.

The SARS-CoV-2 virus initiates infection via interactions between the viral spike protein and the ACE2 receptors on host cells. Variants of concern have mutations in the spike protein that enhance ACE2 binding affinity, leading to increased virulence and transmission. Viral RNAs released after entry into host cells trigger interferon-I (IFN-I) mediated inflammatory responses for viral clearance and resolution of infection. However, overreactive host IFN-I responses and pro-inflammatory signals drive COVID-19 pathophysiology and disease severity during acute infection. These immune abnormalities also lead to the development of post-COVID syndrome if persistent. Novel therapeutics are urgently required to reduce short- and long-term pathologic consequences associated with SARS-CoV-2 infection. Apabetalone, an inhibitor of epigenetic regulators of the BET protein family, is a candidate for COVID-19 treatment via a dual mechanism of action. In vitro, apabetalone downregulates ACE2 gene expression to limit SARS-CoV-2 entry and propagation. In pre-clinical models and patients treated for cardiovascular disease, apabetalone inhibits expression of inflammatory mediators involved in the pathologic cytokine storm (CS) stimulated by various cytokines. Here we show apabetalone treatment of human lung epithelial cells reduces binding of viral spike protein regardless of mutations found in the highly contagious Delta variant and heavily mutated Omicron. Additionally, we demonstrate that apabetalone counters expression of pro-inflammatory factors with roles in CS and IFN-I signaling in lung cells stimulated with SARS-CoV-2 RNA. Our results support clinical evaluation of apabetalone to treat COVID-19 and post-COVID syndrome regardless of the SARS-CoV-2 variant.

COVID

Children enter out-of-home care (OOHC) having experienced significant childhood adversities and trauma. Little is known about the short-term impacts of the COVID-19 pandemic on this vulnerable group. To gain some insights, we analysed the early impacts on the well-being and experiences of children in OOHC and their carers using the Pathways of Care Longitudinal Study data prior to and post the first lockdown restrictions. A total of 862 children, young people and their carers were interviewed either pre-COVID-19 restrictions (n = 567) (April 2019-March 2020) or post-COVID-19 restrictions (n = 295) (June-December 2020). While the two groups showed no significant differences in socio-emotional well-being, both the pre- and the post-COVID-19 restriction groups of children in OOHC had slight reductions in socio-emotional well-being. The interviews with the post-COVID-19 group showed that the pandemic restrictions affected children's well-being and behaviour, education, social and physical activities, as well as time spent with their birth family. Likewise, interviews with carers post-COVID-19 found a negative effect on carers' well-being, their ability to manage financially and their capacity to care and access services and support. The article contributes new evidence to inform OOHC policy and practice to support service systems facing unique challenges arising from a pandemic.

COVID‐19: Impact on children living in out‐of‐home care and their carers

Children enter out‐of‐home care (OOHC) having experienced significant childhood adversities and trauma. Little is known about the short‐term impacts of the COVID‐19 pandemic on this vulnerable group. To gain some insights, we analysed the early impacts on the well‐being and experiences of children in OOHC and their carers using the Pathways of Care Longitudinal Study data prior to and post the first lockdown restrictions. A total of 862 children, young people and their carers were interviewed either pre‐COVID‐19 restrictions (n = 567) (April 2019–March 2020) or post‐COVID‐19 restrictions (n = 295) (June–December 2020). While the two groups showed no significant differences in socio‐emotional well‐being, both the pre‐ and the post‐COVID‐19 restriction groups of children in OOHC had slight reductions in socio‐emotional well‐being. The interviews with the post‐COVID‐19 group showed that the pandemic restrictions affected children's well‐being and behaviour, education, social and physical activities, as well as time spent with their birth family. Likewise, interviews with carers post‐COVID‐19 found a negative effect on carers' well‐being, their ability to manage financially and their capacity to care and access services and support. The article contributes new evidence to inform OOHC policy and practice to support service systems facing unique challenges arising from a pandemic. [ FROM AUTHOR]

Breaking boundaries: Pan BETi disrupt 3D chromatin structure, BD2-selective BETi are strictly epigenetic transcriptional regulators.

BACKGROUND: Bromodomain and extraterminal proteins (BETs) are more than just epigenetic regulators of transcription. Here we highlight a new role for the BET protein BRD4 in the maintenance of higher order chromatin structure at Topologically Associating Domain Boundaries (TADBs). BD2-selective and pan (non-selective) BET inhibitors (BETi) differentially support chromatin structure, selectively affecting transcription and cell viability. METHODS: Using RNA-seq and BRD4 ChIP-seq, the differential effect of BETi treatment on the transcriptome and BRD4 chromatin occupancy of human aortic endothelial cells from diabetic patients (dHAECs) stimulated with TNFα was evaluated. Chromatin decondensation and DNA fragmentation was assessed by immunofluorescence imaging and quantification. Key dHAEC findings were verified in proliferating monocyte-like THP-1 cells using real time-PCR, BRD4 co-immunoprecipitation studies, western blots, proliferation and apoptosis assays. FINDINGS: We discovered that 1) BRD4 co-localizes with Ying-Yang 1 (YY1) at TADBs, critical chromatin structure complexes proximal to many DNA repair genes. 2) BD2-selective BETi enrich BRD4/YY1 associations, while pan-BETi do not. 3) Failure to support chromatin structures through BRD4/YY1 enrichment inhibits DNA repair gene transcription, which induces DNA damage responses, and causes widespread chromatin decondensation, DNA fragmentation, and apoptosis. 4) BD2-selective BETi maintain high order chromatin structure and cell viability, while reducing deleterious pro-inflammatory transcription. INTERPRETATION: BRD4 plays a previously unrecognized role at TADBs. BETi differentially impact TADB stability. Our results provide translational insight for the development of BETi as therapeutics for a range of diseases including CVD, chronic kidney disease, cancer, and COVID-19.

A Targeted Literature Search and Phenomenological Review of Perspectives of People with Multiple Sclerosis and Healthcare Professionals of the Immunology of Disease-Modifying Therapies.

INTRODUCTION: The mechanisms of action of disease-modifying therapies (DMTs) for multiple sclerosis (MS) are complex and involve an interplay of immune system components. People with MS (PwMS) may lack a clear understanding of the immunological pathways involved in MS and its treatment; effective communication between healthcare professionals (HCPs) and PwMS is needed to facilitate shared decision-making when discussing the disease and selecting DMTs and is particularly important in the coronavirus disease 2019 (COVID-19) era. METHODS: In this patient-authored two-part review, we performed a targeted literature search to assess the need for better communication between HCPs and PwMS regarding treatment selection, and also conducted a qualitative survey of four patient and care-partner authors to obtain insights regarding their understanding of and preferences for the treatment and management of MS. RESULTS: Following a search of the Embase and MEDLINE databases using Ovid in June 2020, an analysis of 40 journal articles and conference abstracts relating to patient empowerment and decision-making in DMT selection for MS showed a preference for safety and efficacy of treatments, followed by autonomy and convenience of administration. A need for better communication between HCPs and PwMS during treatment selection to improve patient satisfaction was also identified. The open survey responses from the patient authors revealed a need for greater involvement in decision-making processes and desire for improved communication and information tools. CONCLUSIONS: This targeted literature search and phenomenological review confirms PwMS preferences for empowered decision-making in disease management and treatment selection, to optimize independence, safety, and efficacy. It also identifies an unmet need for improved communication and information tools that convey MS information in a relatable manner. Furthermore, this review seeks to address this unmet need by providing plain language figures and descriptions of MS immune mechanisms that can be used to facilitate discussions between HCPs and PwMS.

In multiple sclerosis (MS), there are different cells in the immune system that contribute to the disease. The main cells in the immune system are T and B cells. People with MS (PwMS) might not be familiar with details about the immune system, and healthcare professionals might not always communicate details about how treatments work clearly to PwMS when choosing treatments with them. It is important for PwMS to have all the information they need to help make decisions about treatments. This information needs to be given in a way they can understand. This is especially important during the coronavirus disease 2019 (COVID-19) pandemic. In this paper, we first looked at what research has already been published about what is most important to PwMS when making treatment decisions. The existing research says that safety and effectiveness are the most important things and that PwMS prefer treatments that they can take themselves. PwMS also need better communication and information from doctors to make decisions and to help explain how MS treatments work in the body. Next, we gave a survey to the patients who are authors of this paper to ask about what is important to them when making treatment decisions. Their answers were very similar to the existing research. Overall, PwMS need better communication from healthcare professionals about the immune system. This paper also includes plain language descriptions and figures to help healthcare professionals explain and discuss the importance of the immune system in MS with PwMS.

Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro.

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics.

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

Non-invasive Thoracic Impedance Changes in COVID-19 Pulmonary Infection.

Graphical abstract.