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Background/Introduction: Hyperinflammatory responses to SARS-CoV-2 can cause myocarditis and cardiac dysfunction including congestive heart failure [1]. SARS-CoV-2 RNA induces type I interferon (IFN-I), activating IFN regulatory factors (IRFs) and downstream IFN stimulated genes (ISGs) to initiate inflammatory processes. SARS-CoV-2 variants may develop immune escape, undercutting benefits of vaccinations. These challenges highlight the need of variant-independent therapies to improve COVID-19 outcomes. Apabetalone is an epigenetic BD2-selective BET inhibitor in phase 3 trials for cardiovascular disease [2]. Apabetalone has the potential to treat COVID-19. It counters inflammatory signals caused by cytokine storm (CS), preventing cardiac dysfunction associated with severe COVID-19 symptoms in cardiac organoids [3]. It also downregulates angiotensin-converting enzyme 2 (ACE2) expression, the main host cell receptor for SARS-CoV-2 spike protein thus impeding propagation of wild-type SARS-CoV-2 [3,4]. Purpose: 1) Evaluate apabetalone's effect on inflammatory processes induced by viral-RNA mimetic in human lung cells;2) Assess apabetalone's ability to prevent binding of the highly contagious delta variant spike protein to human lung cells. Methods: Inflammatory gene expression was examined by real-time PCR in apabetalone treated human bronchial epithelial cells (Calu-3) stimulated with poly I:C, a well-accepted viral RNA mimetic that elicits inflammatory signals similar to SARS-CoV-2 RNA [5]. Binding of SARS-CoV-2 delta or wild-type spike protein to apabetalone treated Calu-3 cells was determined by flow cytometry. Results: In Calu-3 cells, apabetalone dose-dependently downregulated poly I:C induced transcription of key COVID-19 associated cytokines (IL6, CXCL10, CCL2) to a similar extent as baricitinib (up to 86%, p<0.0001), an anti-inflammatory agent in emergency use for COVID-19 treatment. Moreover, apabetalone but not baricitinib diminished IL1B mRNA levels (up to 66%, p<0.0001). Apabetalone and baricitinib opposed poly I:C induced expression of IFNB1 (an IFN-I), IRF1 and IRF9 (upstream regulators) as well as IFIT1 and IFIT2 (downstream ISGs that regulate CXCL10 expression;up to 90%, p<0.0001). Clinically relevant doses of apabetalone did not alter expression of anti-viral IFITM2, an ISG that blocks SARS-CoV-2, particularly omicron, endosomal entry [6]. Therefore, apabetalone counters the expression of inflammatory factors with roles in CS and IFN-I signaling in response to poly I:C. Additionally, apabetalone reduced delta and wild-type spike protein binding to unstimulated Calu-3 cells (up to 72%, p<0.0001). Conclusions: Apabetalone's dual anti-viral and anti-inflammatory mechanism positions it as a variant-independent COVID-19 therapeutic. Together with an established safety profile from >2000 treatment-years with apabetalone, the data provide rationale for an ongoing clinical trial (NCT04894266) which includes analysis of cardiac damage. Funding Acknowledgement: Type of funding sources: Private company. Main funding source(s): Resverlogix Corp
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Introduction: COVID-19, the infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), often presents with a spectrum of symptoms at varying levels of severity, ranging from asymptomatic patients to those with fatal complications, such as myocarditis. With increased availability of COVID-19 vaccines, the awareness of possible side effects has expanded as reports surface. This study reviewed cases of myocarditis following COVID-19 vaccination and with existing literature on COVID-19 infection-induced myocarditis to compare clinical courses and analyze possible mechanisms of action. Methods: A systematic review of literature was conducted to identify published case reports (as of February 3, 2022) pertaining to the development of myocarditis following COVID-19 vaccination with either Pfizer or Moderna for an in-depth analysis. Additional subgroup analyses were conducted based on age, past medical history, vaccine manufacturer, and dose number. Results: There were 53 eligible case reports that were included in this study. Patients were mostly male with a median age of 24 years, and the most reported symptom upon presentation was chest pain. Seventy percent of the cases involved the Pfizer vaccine with a majority of myocarditis developing subsequent to second dose. Resolution of symptoms was achieved in all but one patient. Clinical severity, as measured primarily by left ventricular ejection fraction, appeared to be worse among adult patients than pediatric, as well as for patients with comorbidities. Conclusion: This study revealed an observable association between COVID-19 vaccines and myocarditis. However, the clinical course and prognosis seem favorable and less prevalent than those conferred from natural infection.
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Methods: We reviewed reports of post COVID dysautonomia and management strategies pursued to understand best practices and provide a primer for clinicians to guide patient management. We reviewed the literature for case reports of post COVID dysautonomia and compiled the cases into a table. Treatment approaches and outcomes were aggregated into an algorithm for management guidance. Results: Ten studies regarding post COVID dysautonomia were reviewed. Strategies included conservative approaches such as fluids, salt consumption, compression stockings, abdominal binders and head of bed elevation as well as strength building such as yoga, resistance exercise, and recumbent physical activity. Moreover, psychosocial support including cognitive behavioral therapy, biofeedback, and support groups were emphasized along with pharmacologic remedies such as midodrine, ivabradine, fludrocortisone, intravenous immunoglobulin, gabapentin, and topical lidocaine in additoin to interventions such as enhanced external counterpulsation. Primary and secondary outcomes included self-report surveys, autonomic laboratory testing, hand grip strength and heart rate variability. Background: Growing numbers of cases of dysautonomia after acute COVID-19 infection are being reported involving previously healthy patients. This post-COVID dysautonomia is predominantly characterized by lingering neurologic and cardiovascular dysfunction including tachycardia, orthostatic intolerance, migraine, exercise intolerance, fatigue, and cognitive impairment. Anxiety, insomnia, and uncertainty surrounding the COVID-19 pandemic present additional risk factors for sympathetic overdrive and deconditioning. Best management strategies and practice guidelines for this patient population remains unknown. Conclusion: Our review suggests consideration of an integrative, multimodal treatment approach involving physical activity, mental well-being, nutrition, stress management, and medication. These primarily facilitate management of dysautonomia, but rarely lead to complete symptom resolution. Despite the uncertainty associated with post-COVID dysautonomia, patient validation, education, and lifestyle approaches provide the cornerstone of management. Since post-COVID dysautonomia will comprise an increasing number of care consultations, clinician awareness, prompt diagnosis, and personalized management are essential.
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Background/Introduction: SARS-CoV-2 causes life threatening COVID- 19 complications including acute coronary syndrome, venous thromboembolism, hyperinflammation and damage in multiple tissues. The SARSCoV- 2 spike protein binds cell surface receptors including angiotensinconverting enzyme 2 (ACE2) for entry into host cells to initiate infection. Host cell dipeptidyl peptidase-4 (DPP4 / CD26) is implicated as a cofactor in uptake. Recent evidence indicates expression of factors involved in SARS-CoV-2 uptake into host cells is regulated by BET proteins, epigenetic readers modulating gene expression. Apabetalone, the most clinically advanced BET inhibitor (BETi), is in phase 3 trials for cardiovascular disease (CVD) (a, b). In cultured human cardiomyocytes, apabetalone suppressed infection with SARS-CoV-2 and prevented dysfunction of cardiac organoids induced by the cytokine-storm that arises in patients with severe symptoms (c). However, anti-viral properties of apabetalone in other cell types are not known. Purpose: To examine effects of apabetalone on SARS-CoV-2 infection in cell culture via downregulated expression of cell surface receptors involved in viral entry. Cell systems used mimic initial sites of infection in the lung as well as cell types contributing to complications in late stages of infection. Methods: Gene expression was measured by real-time PCR, protein levels by immunoblot or flow cytometry, and binding of recombinant SARSCoV- 2 spike protein by flow cytometry. Infection with SARS-CoV-2 was determined in a BSL3 facility. Infectivity was quantified by determining levels of viral spike protein amongst total cells via imaging on an Operetta CLS. Results: In Calu-3, a human bronchial epithelial cell line, apabetalone dose-dependently downregulated ACE2 gene expression (up to 98%), reduced ACE2 protein levels (up to 84%) and diminished binding of SARSCoV- 2 spike protein (up to 77%, p<0.001 for all parameters). Further, apabetalone abolished infection of Calu-3 cells with live SARS-CoV-2, which was comparable to other antiviral agents. Apabetalone-driven ACE2 downregulation was also observed in extrapulmonary cell types including HepG2, Huh-7 or primary hepatocytes (up to 90%, p<0.001 for all cell types), and Vero E6, a monkey kidney epithelial cell line (up to 38%, p<0.05). DPP4/CD26, a potential cofactor for SARS-CoV-2 uptake, was also downregulated by apabetalone in Calu-3 cells (mRNA ∼65% and protein ∼40%, p<0.001), which may be synergistic with ACE2 reductions to impede SARS-CoV-2 infection. Conclusions: Apabetalone, an investigational drug for CVD, reduced cell surface receptors (ACE2 and DPP4) involved in SARS-CoV-2 uptake into host cells and dramatically attenuated SARS-CoV-2 infection/propagation in vitro. Our results suggest apabetalone can mitigate SARS-CoV-2 replication in multiple organs, which together with an established safety profile supports clinical evaluation of apabetalone to treat.
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Covid-19 restrictions impacted many people’s daily lives through infection, fear of infection and restrictions on movement. This re-issue of a questionnaire sought to examine the impact of Covid-19 restrictions on frequency of physical activity, participation in sports, wellbeing and symptoms of anxiety and depression in Irish adolescents. 3,021 adolescents from 61 post-primary schools in the Republic of Ireland completed questionnaires. Consistent with findings from a previous issue of the questionnaire, conducted pre-Covid-19, a minority of adolescents were found to meet the WHO’s physical activity guidelines (11.6% of males and 5.2% of females) although there were large decreases in 1st year males and females. Adolescents reporting elevated symptoms of depression increased from 39% to 46% with almost 3 in 5 females reporting symptoms of depression ranging from mild to extreme. Highest levels of wellbeing were found in adolescents who participated in 3 or more sports, although there was an 8% reduction in the amount of adolescents participating in 3 or more sports. There were no changes in physical activity levels overall, despite changes within sub-groups and patterns of physical activity. There was a clear increase in symptoms of depression, with females impacted more than males. Previously active individuals were more likely to increase activity and therefore report higher levels of mental health while those who were less active were more likely to decrease activity and report lower mental health. Future interventions should seek to target adolescents currently inactive or with low levels of activity as they are most at risk of further reductions and the associated negative health implications. © 2021 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.
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Background/AimsCOVID-19 lockdown affected access to clinical care for manyvulnerable patients, including those with inflammatory arthritis (IA). Italso had the potential to alter self-management behaviours. Thesechanges could in turn impact mental health, especially given that IApatients are already at higher risk of mental health disorders. Thus, theaims of this study were to determine how IA care and self-management were affected by lockdown and assess the impact of thesechanges on disease outcomes and mental health.MethodsOnline questionnaires were completed by 338 participants betweenJune and July 2020. The questionnaires assessed demographics, IAcondition, IA self-management, COVID-19 clinical information, qualityof life, and mental health. Visual analogue scale (VAS) scores forpatient global assessment (PGA) of disease activity, pain, fatigue, andemotional distress were completed relating to the previous week andretrospectively for pre-lockdown (March) and early-lockdown (April).Improvement/worsening in each VAS was considered as a change of10 points or more from pre-lockdown to the current rating. Linearregressions were conducted to determine factors associated withworse outcomes, controlling for potential confounders including selfreported pre-lockdown status.ResultsMean VAS scores worsened during lockdown for all outcomemeasures, with over half reporting a more than 10-point worsening(Table 1). Changes to clinical care affected 87% of patients. The mostcommonly affected services were hospital outpatient appointments(77%), GP appointments (59%), and blood tests (53%). Changes toclinical care were significantly associated with worse PGA (b = 8.95, p=0.01), pain (b = 7.13, p=0.05), fatigue (b = 17.01, p<0.00) andemotional distress (b = 12.78, p<0.01). Regarding self-management, 64% of patients reported changes to diet while 51% reduced physicalactivity. Change in diet was not significantly associated with any of theoutcomes, whereas physical activity was associated with PGA (b=-2.42, p<0.01), pain (b=-2.43, p<0.01), fatigue (b=-2.5, p < 0.01), andemotional distress (b=-2.41, p<0.01).ConclusionMost patients (87%) had at least one area of clinical care affected bythe lockdown. These changes in IA clinical care were associated withworse disease outcomes across all measures and greater emotionaldistress. In self-management, reduced physical activity was associated with worse outcomes in all physical and mental healthmeasures.
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Background/AimsInflammatory arthritis (IA) patients have been identified as being atgreater risk of severe illness from COVID-19. It is likely that lockdownrestrictions enforced by the UK government in response to the COVID-19 pandemic, and subsequent changes made to healthcare provisions, could impact patients' abilities to effectively manage theircondition. The aim of this study was to qualitatively explore the impact of COVID-19 and lockdown on self-management behaviours andhealthcare provision in people with IA.MethodsSemi-structured interviews were conducted with 21 patients with IAfrom across the UK (as part of a larger longitudinal survey studyexploring the impact of COVID-19 on health-related quality of life forpeople with IA). Participants who gave consent for contact, followingthe completion of the baseline survey study, were approached to takepart in the qualitative interviews. The interview schedule wasdeveloped with a Patient Research Partner and consisted of eightmain questions to explore participants' experiences of the COVID-19pandemic, including the impact of COVID-19 on their self-management behaviours and access to healthcare services. The interviewswere conducted via telephone and were recorded and transcribedbefore being analysed using inductive thematic analysis.ResultsParticipants were aged between 24-72 (mean age 50.0, SD 15.6) andwere mostly female (71%) and White British (86%). Four main themeswere identified: impact of COVID-19 on medication adherence, impactof COVID-19 on physical activity, impact of COVID-19 on diet, andimpact of COVID-19 on healthcare access. Subthemes focused onpositive and negative changes made to these areas, as well asbehaviours which remained consistent. Some participants expressedthat the lockdown period had enabled them to increase their physicalactivity, improve their diet and maintain their usual medicationregimen, whilst others noted that lockdown had had a negativeimpact on their self-management behaviours. For example, somepatients decided to discontinue their medication during the pandemicdue to concerns that it would make them more susceptible to severeconsequences from COVID-19. In relation to healthcare provision, themost commonly reported change was the introduction of telephoneappointments to replace face-to-face consultations. Several patientsfound the telephone appointments ineffective, especially if theirdisease was relatively uncontrolled. Nevertheless, participants understood why a remote approach had been implemented during thepandemic.ConclusionCOVID-19 has had an impact on patients' abilities to manage their IA.Healthcare professionals need to recognise the impact of COVID-19on patient self-management and healthcare provision to ensure thatadequate understanding and support is available to patients who mayhave inadequate disease control as a result.
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Background/AimsCOVID-19 lockdown has affected the mental health of many peoplearound the world. People with inflammatory arthritis (IA) are at a higherrisk of mental health and psychosocial consequences of the pandemiccompared with the general population, since they are potentially morevulnerable to COVID-19 and experience higher rates of existingcomorbid mental health disorder. Furthermore, vulnerable patientswere advised to self-isolate for 12 weeks, which could furtherexacerbate emotional distress. This study aimed to explore theimpacts of lockdown on mental health and wellbeing, and to determinewhich factors were associated with worse disease outcomes.MethodsAn online questionnaire was completed by 338 participants in the UKwith an IA condition between June and July 2020. The questionnaire, designed with input from a service user, assessed various aspects ofthe impact of the pandemic on the quality of life of people with IA, including their mental health. Self-reported visual analogue scales(VAS) for patient global assessment (PGA) of disease activity, pain, fatigue, and emotional distress were completed relating to theprevious week, and retrospectively for pre-lockdown (March) andearly-lockdown (April). Specific mental health outcomes were furthercaptured using the 8-item Patient Health Questionnaire (PHQ8) and theshort UCLA loneliness scale. Linear regressions were conducted todetermine mental health factors associated with worse outcomes onphysical health measures (PGA, pain, and fatigue), controlling for fearof COVID-19 and COVID-19 status.ResultsOverall, 49% of participants met the PHQ8 criteria for moderate tosevere depressive symptoms and 58% reported their mental healthhad worsened by more than 10 points on the emotional distress VASduring lockdown. Finally, 37% reported they were concerned aboutloneliness, with 26% indicating this had worsened during lockdown.Emotional distress VAS was significantly associated with PGA(b = 0.21, p< 0.01), pain (b = 0.24, p<0.01), and fatigue (b = 0.36, p<0.01). Similarly, depression was also associated with PGA (b = 0.95, p<0.01), pain (b = 0.92, p<0.01), and fatigue (b = 1.56, p<0.01).However, loneliness was not associated with any of the physicalhealth VAS scores but was associated with the emotional distress VAS(b = 1.83, p=0.00). These results remained consistent for emotionaldistress, depression, and loneliness as predictors when accounting forfear of COVID-19 and COVID-19 status.ConclusionThere has been a clear impact of the pandemic on the mental health ofpeople with IA, and this should be taken into consideration byclinicians, especially as it appears to be related to worse overallreported physical health. The mixed results for loneliness in comparison to other mental health measures may illustrate the interrelatedness of these aspects of mental and physical health, particularlyin the context of lockdown.
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The COVID-19 pandemic saw sudden measures to stop the spread of the virus, closing schools and forcing a shift to remote learning. This study examines the emotions exhibited by students around factors of online learning as they transitioned abruptly from in-person instruction. Student responses to a New York Times writing prompt in March 2020 were analyzed using frequencies and epistemic network analysis (ENA) models. About half of the responses contained positive emotional valence, but more than three quarters had negative emotional valence. The strongest connection was observed between negative emotional valence for instructional format and focus. More specifically, anxiety between the format, focus, and workload were strongly connected, indicative of the difficulties faced by students to maintain focus and balance assignments on learning activities while being at home. At the same time, there was a significant connection between positive and negative emotional valence regarding the instructional format, attributed to mixed and changing emotions with adjusting to online learning. When students did exhibit positive emotions, it was interest in the instructional format linked with interest in schedule, indicating that the scheduling flexibility of the online format was the factor students liked most. © 2021, Springer Nature Switzerland AG.
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New York City is in the grip of the COVID-19 pandemic. Health care centers are stretched beyond capacity. Daily death rates are staggering. The city's population is hunkered down in fear. Our anxiety treatment center is treating patients via video appointments. We are helping anxious individuals adapt to tumultuous changes that we ourselves are experiencing. Our work in this time has reinforced our core beliefs about managing one's emotions; that difficult times require more active coping and that we all draw heavily from social support and familiarity to create a feeling of well-being. These principles and the experiences of our patients are discussed.