Mouse Adapted SARS-CoV-2 Model Induces "Long-COVID" Neuropathology in BALB/c Mice (preprint)

The novel coronavirus SARS-CoV-2 has caused significant global morbidity and mortality and continues to burden patients with persisting neurological dysfunction. COVID-19 survivors develop debilitating symptoms to include neuro-psychological dysfunction, termed "Long COVID", which can cause significant reduction of quality of life. Despite vigorous model development, the possible cause of these symptoms and the underlying pathophysiology of this devastating disease remains elusive. Mouse adapted (MA10) SARS-CoV-2 is a novel mouse-based model of COVID-19 which simulates the clinical symptoms of respiratory distress associated with SARS-CoV-2 infection in mice. In this study, we evaluated the long-term effects of MA10 infection on brain pathology and neuroinflammation. 10-week and 1-year old female BALB/cAnNHsd mice were infected intranasally with 104 plaque-forming units (PFU) and 103 PFU of SARS-CoV-2 MA10, respectively, and the brain was examined 60 days post-infection (dpi). Immunohistochemical analysis showed a decrease in the neuronal nuclear protein NeuN and an increase in Iba-1 positive amoeboid microglia in the hippocampus after MA10 infection, indicating long-term neurological changes in a brain area which is critical for long-term memory consolidation and processing. Importantly, these changes were seen in 40-50% of infected mice, which correlates to prevalence of LC seen clinically. Our data shows for the first time that MA10 infection induces neuropathological outcomes several weeks after infection at similar rates of observed clinical prevalence of "Long COVID". These observations strengthen the MA10 model as a viable model for study of the long-term effects of SARS-CoV-2 in humans. Establishing the viability of this model is a key step towards the rapid development of novel therapeutic strategies to ameliorate neuroinflammation and restore brain function in those suffering from the persistent cognitive dysfunction of "Long-COVID".

The effects of COVID-19 on cognitive performance in a community-based cohort: A COVID Symptom Study Biobank observational study (preprint)

Background Cognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored. Methods Cognitive performance (working memory, attention, reasoning, motor control) was assessed in participants of a voluntary biobank in July, 2021 (Round 1), and April, 2022 (Round 2). Participants, drawn from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds. Findings 3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, {beta} = -0.14 standard deviations, SDs) than negative controls. Deficits were largest for positive individuals with [≥] 12 weeks of symptoms (N = 495, {beta} = -0.22 SDs). Effects were comparable to hospital presentation during illness (N = 281, {beta} = -0.31 SDs), and 10 years age difference (60-70 years vs. 50-60 years, {beta} = -0.21 SDs) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection. Interpretation Cognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms. Funding Chronic Disease Research Foundation, Wellcome Trust, National Institute for Health and Care Research, Medical Research Council, British Heart Foundation, Alzheimer's Society, European Union, COVID-19 Driver Relief Fund, French National Research Agency.

Post COVID-19 conditions in Children and Adolescents at 3 months following a Delta outbreak in Australia: a cohort study (preprint)

Background: Long COVID remains incompletely understood in children and adolescents with scant Australian data available. We aimed to assess the impacts of the 2021 Delta variant of SARS-CoV-2 outbreak on symptoms and functioning 12 weeks post-acute infection in a cohort of children and adolescents. Methods: The parents (or next of kin) of 11864 children and adolescents from a population catchment who had mandatory contact with Sydney Childrens Hospital Network facilities during acute SARS-CoV-2 infection (confirmed by PCR) were contacted by email or text message. Findings: 1731 (17.7%) responded to an online survey assessing symptoms, functional impairment. 203 of the responders (11.7%) gave answers that were consistent with continued symptoms and/or functional impairment and were flagged for clinical review. Of the 169 subsequently clinically reviewed, many had already recovered (n=63, 37.3%) or had a pre-existing condition exacerbated by COVID-19 (18, 10.7%); 64 (37.9%) were diagnosed with a Post COVID Condition (PCC). Of these, a minority we considered to have features compatible with the United Kingdom consensus cases definition for Long COVID (n=21). Interpretation: During an outbreak of the Delta variant of SARS-CoV-2 an online questionnaire with subsequent clinical review revealed self-reported non-recovery at 12 weeks in a minority of cases, with a spectrum of features. Long COVID comprised only a subset of cases with self-reported non-recover, is infrequent in children and adolescents, but still comprises a likely significant burden that warrants attention.

Treatment of Long COVID symptoms with triple anticoagulant therapy (preprint)

Background: Fibrin(ogen) amyloid microclots and platelet hyperactivation are key pathological findings in patients with acute COVID-19 infection and also in those with Long COVID/Post-Acute Sequelae of COVID-19 (PASC). These pathologies may represent a suitable target for pharmacological treatment of Long COVID.  Methods: Here we report on the symptoms displayed by a cohort of 91 South African Long COVID patients at baseline and after a clinician-initiated anticoagulant regime was completed. For laboratory analysis, patients provided a blood sample before and after treatment. Fibrinaloid microclot presence was studied by adding thioflavin T to platelet poor plasma (PPP), whilst platelet hyperactivation was studied using two platelet markers- PAC1 and CD62P (P-selectin). The anticoagulant regime included dual antiplatelet therapy (DAPT- Clopidogrel 75mg + Aspirin 75mg) once a day, and a direct oral anticoagulant (DOAC- Apixaban) 5mg twice a day. A proton pump inhibitor (PPI) pantoprazole 40 mg/day was also prescribed for gastric protection. Each of the treated cases reported their main Long COVID symptoms, and whether their symptoms resolved following treatment or not.  Results: In our cohort a most participants did not report any comorbidities before acute COVID-19 infection. Hypertension and dyslipidaemia were the commonest underlying illnesses, whilst the most commonly reported Long COVID symptoms included fatigue, cognitive dysfunction, shortness of breath, and joint and muscle pains. Following completion of treatment, each of the different symptoms resolved in the majority of patients. This was also reflected in the laboratory analysis, where a decrease in the severity of fibrin amyloid microclotting and the degree of platelet pathology was noted. No serious adverse bleeding events were reported.  Conclusions: Fibrin amyloid microclots, platelet hyperactivation/ aggregation, and  widespread endothelialitis inhibit the transport of oxygen at a capillary/cellular level. This provides a ready explanation for the symptoms of Long COVID. By normalizing the failed clotting physiology and reversal of the endothelialitis, triple anticoagulant therapy represents a promising treatment option that appears to be highly efficacious, and warrants controlled clinical studies. We caution that such a regime must only be followed under expert medical supervision in view of the risk of  bleeding.

Use of a digital application to enhance communication and triage between care homes and National Health Service community services in the United Kingdom: a qualitative evaluation (preprint)

Recent years have seen a rise in digital interventions to improve coordination between care homes and NHS services, supporting remote sharing of data on the health of care home residents. Such interventions were key components in the response to the COVID-19 pandemic. This paper presents findings from the qualitative component of an evaluation of an implementation of the HealthCall Digital Care Homes application, across sites in northern England. The implementation commenced prior to the pandemic and continued throughout. Semi-structured, qualitative interviews were held with stakeholders. Interviews were conducted remotely (October 2020 -June 2021). Data were analysed via a reflexive thematic analysis then mapped against Normalization Process Theory (NPT) constructs (coherence, collective action, cognitive participation, and reflexive monitoring) providing a framework to assess implementation success. Thirty-five participants were recruited: 16 care home staff, six NHS community nurses, five relatives of care home residents, four HealthCall team members, three care home residents, and one local authority commissioner. Despite facing challenges such as apprehension towards digital technology among care home staff, the application was viewed positively across stakeholder groups. The HealthCall team maintained formal and informal feedback loop with stakeholders. This resulted in revisions to the intervention and implementation. Appropriate training and problem solving from the HealthCall team and buy-in from care home and NHS staff were key to achieving success across NPT constructs. While this implementation appears broadly successful, establishing rapport and maintaining on-going support requires significant time, financial backing, and the right individuals in place across stakeholder groups to drive implementation and intervention evolution. The digital literacy of care home staff requires encouragement to enhance their readiness for digital interventions. The COVID-19 pandemic has pushed this agenda forward. Problems with stability across the workforce within care homes need to be addressed to avoid skill loss and support embeddedness of digital interventions.

The impact of the COVID-19 pandemic on the residential aged care sector, responses and recommendations: A systematic scoping review (preprint)

Objective: This systematic scoping review sought to identify the impact of the COVID-19 pandemic on the residential aged care (RAC) sector, its system components, and the range of COVID-19 response strategies across the sector.  Methods: ProQuest, PubMed, CINAHL, Google Scholar and Cochrane Central were searched April-August 2022 for peer reviewed articles and grey literature. One hundred and forty six articles on the impact of the COVID-19 pandemic on the RAC sector and sector interventions/policy responses are included in this review.  Results:The World Health Organization’s (WHO) six building blocks of health systems were used to categorise impacts and interventions. The COVID-19 pandemic generally highlighted poor resourcing of the RAC sector and exacerbated workforce shortages; led to increased workload, changes in job demand and declines in worker mental health; revealed poor integration across health and aged care sectors and reduced advance care and palliative care planning. Social restriction measures led to declines in the physical, mental health and cognitive decline of residents in RACFs, in particular those with cognitive impairment. Innovative care models included the introduction of outreach teams and primary care models for RACFs and increased use of telehealth and videoconferencing for social engagement, although there was mixed evidence on the use of telehealth for people with cognitive impairment. Discussion: Additional funding of the RAC sector is required to boost workforce numbers and training, and support worker mental health, along with policies which attract, maintain and support workers from culturally and linguistically diverse (CALD) backgrounds. COVID-19 response strategies in RACFs need to ensure that all residents have access to resources such as telehealth for health and social engagement, including residents with cognitive impairment. Clear guidelines and additional resourcing are required for utilisation of telehealth during a pandemic. Additional research on appropriate COVID-19 responses for residents with cognitive impairment is required, along with a balance between infection prevention and control and social engagement strategies.

Impact of the COVID-19 Pandemic Crisis on Turnover Intention Among Nurses in Emergency Departments in Thailand: A Cross Sectional Study (preprint)

Background: During the COVID-19 pandemic in Thailand, a large volume of COVID-19 patients was referred to hospital emergency departments (EDs). This increased job demand and job strain among ED nurses, resulting in a high risk for intention to leave their organization. This study had two aims: 1) to investigate turnover intention during the COVID-19 pandemic among ED nurses; and 2) examine the effect of organization resources, maladaptive regulation, and job burnout on nurses’ turnover intention. Method: This cross sectional study investigated 322 ED nurses. We divided participants into two groups: dark-red zone areas (pandemic crisis areas) and non-red zone areas (non-pandemic crisis areas). Descriptive statistics, Pearson’s correlation analysis, and multiple linear regression (stepwise method) were used to analyze factors that predicted turnover intention. Results: Most participants were female and the mean age was 34.54 years. Overall, the mean score for the Turnover Intention Scale was 18.27±4.69 and 72.8% of ED nurses in dark-red zone areas desired to leave their organization. During the pandemic, motivation, exhaustion, and cognitive impairment positively influenced turnover intention among ED nurses in dark-red zone areas. Low availability of organization resources was associated with an increase in the turnover intention rate. Maladaptive regulation, exhaustion, and cognitive impairment positively influenced turnover intention among ED nurses in non-red zone areas. Conclusion: Exhaustion and cognitive impairment are important dimensions of burnout that are associated with turnover intention among ED nurses. We suggest that promoting safe workplace environments and implementing interventions to reduce job demand and job strain for ED nurses may reduce turnover intention.

A Study on the Nostalgia effect of Dance for All Participants during the COVID-19 Pandemic (preprint)

Background: The purpose of this study is to examine the effect of participants' nostalgia for the before COVID-19 DFA experience on their future participation continuation intention. To achieve this purpose, nostalgia, cognitive emotion regulation (CER), coping flexibility (CF), resilience, and participation continuance intention (PCI) were set as major variables and the structural influence relationship between them was explored. Methods: A survey was con-ducted on 557 “dance for all” participants (DFAP’s) who joined public sports facilities, academies, and clubs in Seoul and Gyeonggi Province in South Korea. Data analysis was performed on Windows PC/SPSS 26.0 and AMOS 24.0 ver. frequency analysis, correlation analysis, confirmatory factor analysis and structural equation modeling were used to analyze the survey results. Results: First, all sub-factors of the nostalgia of DFAP’s has a statistically significant effect on CER. Second, CER of DFAP's has a statistically significant effect on CF. Third, CER of DFAP's does not have a statistically significant effect on resilience. Fourth, CF and resilience of DFAP's has a statistically significant effect on PCI. Conclusions: Therefore, this study’s novelty is that it provides practical implications for the application of nostalgia as an alternative to satisfying the desire to participate in physical activities such as DFA during the “post COVID-19”era.

What interventions or best practice are there to support people with Long COVID, or similar post-viral conditions or conditions characterised by fatigue, to return to normal activities: a rapid review (preprint)

Previous research has categorised symptoms of COVID-19 / Long COVID into 12 thematic areas including: fever, myalgia, fatigue, impaired cognitive function, and that COVID-19 survivors had reduced levels of physical function, activities of daily living, and health-related quality of life. Our aim was to review the evidence for interventions or best practice to support people with Long COVID, or similar post-viral conditions characterised by fatigue, to return to normal activities. Evidence was included from guidelines, systematic reviews (SR), and primary studies. The primary studies focussed on Long COVID (LC) indicated that there should be a needs-based focus to care for those with LC. Consideration should be given to individuals living with LC in the same way as people with disabilities are accommodated in terms of workplace adjustment. Two SRs indicated that non-pharmaceutical interventions (NPIs) for patients with LC or chronic fatigue syndrome could help improve function for activities of daily life. However, the third, most recent SR, concluded that there is a lack of robust evidence for NPIs. LC fatigue management methods may be beneficial under certain conditions. One SR reported work capability as an outcome however they did not find any studies which evaluated the impact of interventions on return to work/ normal life. One primary study, on individuals with CFS, described a written self-management programme. Following this intervention there was an 18% increase in the number of patients in employment. Policy and practice implications: Long COVID is still being established as a post-viral condition with many symptoms. Patient-centred treatment options such as occupational therapy, self-management therapy and talking therapy may be considered in the same way as for other debilitating conditions. Return-to-work accommodations are needed for all workers unable to return to full-time employment. Due to the nature of the studies included, there was little reported evidence of effectiveness of getting individuals back into their normal activities.

Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer's disease. (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimer's disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients. In this study, we investigated the levels of Angiotensin I Converting Enzyme 2 (ACE2), the main entry receptor of SARS-COV-2 in cells, in postmortem parietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein and mRNA were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02), markers of pericytes (PDGFR{beta}, p=0.02 and ANPEP, p = 0.007) and caveolin1 (p = 0.03), but positively correlated with soluble amyloid-{beta} peptides (A{beta}) concentrations (p = 0.01) and insoluble phospho-tau (S396/404, p = 0.002). No significant differences in ACE2 were observed in the 3xTgAD mouse model of tau and A{beta} neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is mainly localized in neurons in the human brain but predominantly in microvessels in the mouse brain. The present data show that an AD diagnosis is associated with higher levels of soluble ACE2 in the human brain, which might contribute to a higher risk of CNS SARS-CoV-2 infection.

Validating virtual administration of neuropsychological testing in Parkinson disease: a pilot study (preprint)

Background COVID-19 has highlighted the need for remote cognitive testing. Virtual testing may lessen burden and can reach a larger patient population. The reliability and validity of virtual cognitive testing in Parkinson disease (PD) is unknown.Objectives To validate neuropsychological tests for virtual administration in PD.Methods Participants enrolled in an observational, cognition-focused study completed a rater-administered cognitive battery in-person and via video conference 3–7 days apart. Order of administration was counterbalanced. Analyses to compare performance by type of administration (virtual versus in-person) included paired t-test, intraclass correlation (ICC) and linear mixed-effects models.Results Data for 35 (62.9% male) PD participants (62.5% normal cognition, 37.5% cognitive impairment) were analyzed. Only the semantic verbal fluency test demonstrated a difference in score by administration type, with a significantly better score when administered virtually (paired t-test p = 0.011 and linear mixed-effects model p = 0.012). Only the Dementia Rating Scale-2, Trails A test and phonemic verbal fluency demonstrated good reliability (ICC value 0.75–0.90) for virtual versus in-person administration, and values for visit 1 versus visit 2 were similarly low overall. Trail making tests were successfully administered virtually to only 18 (51.4%) participants due to technical issues.Conclusions Virtual cognitive testing overall is feasible in PD, and virtual and in-person cognitive testing generate similar scores at the group level, but reliability is poor or moderate for most tests. Given that mode of test administration, learning effects and technical difficulties explained relatively little of the low test-retest reliability observed, there may be significant short-term variability in cognitive performance in PD in general, which has important implications for clinical care and research.

Trajectories of Sleep Disturbance and Self-Management of Chronic Conditions during COVID-19 among Middle-aged and Older Adults (preprint)

Background:The COVID-19 pandemic has had a widespread impact on sleep quality, yet little is known about the prevalence of sleep disturbance and its impact on self-management of chronic conditions during the ongoing pandemic. Objective: To evaluate trajectories of sleep disturbance, and their associations with one’s capacity to self-manage chronic conditions. Design: A longitudinal cohort study linked to 3 active clinical trials and 2 cohort studies with 5 time points of sleep data collection (July 15, 2020 – May 23, 2022). Participants: Adults living with chronic conditions who completed sleep questionnaires for two or more time points. Exposure: Trajectories of self-reported sleep disturbance across 5 time points. Main Outcomes: 3 self-reported measures of self-management capacity, including subjective cognitive decline, medication adherence, and self-efficacy for managing chronic disease. Results: 549 adults aged 23 to 91 years were included in the analysis. Two thirds had 3 or more chronic conditions; 42.4% of participants followed a trajectory of moderate or high likelihood of persistent sleep disturbance across the study period. Moderate or high likelihood of sleep disturbance was associated with older age (RR 1.57, 95% CI 1.09, 2.26, P<.05), persistent stress (RR 1.54, 95% CI 1.16, 2.06, P=.003), poorer physical function (RR 1.57, 95% CI 1.17, 2.13, P=.003), greater anxiety (RR 1.40, 95% CI 1.04, 1.87, P=.03) and depression (RR 1.63, 95% CI 1.20, 2.22, P=.002). Moderate or high likelihood of sleep disturbance was also independently associated with subjective cognitive decline, poorer medication adherence, and worse self-efficacy for managing chronic diseases (all P<.001). Conclusions: Persistent sleep disturbance during the pandemic may be an important risk factor for inadequate chronic disease self-management and potentially poor health outcomes in adults living with chronic conditions. Public health and health system strategies might consider monitoring sleep quality in adults with chronic conditions to optimize health outcomes.

Changes in depression and anxiety among people with cognitive impairment and dementia during the COVID-19 pandemic: Analysis of the English Longitudinal Study of Ageing (preprint)

Background: Some studies have identified declines in mental health over the course of the COVID-19 pandemic across the world and in different age groups, including older people. As anxiety and depression are common neuropsychiatric symptoms among people with dementia or mild cognitive impairment, the mental health experiences of older people during the pandemic should therefore take cognitive function into consideration. This should also be examined using quantitative measures that were assessed prior to the pandemic. This study addresses such gaps in the evidence base on depression and anxiety among older people with cognitive impairment before and throughout the COVID-19 pandemic. Methods and Findings: Using data from the English Longitudinal Study of Ageing (ELSA) collected from 2018/19 to Nov/Dec 2020, we estimated changes in depression and anxiety for people aged 50+ in England across three cognitive function groups: no impairment, mild cognitive impairment, and dementia. We found that depression (measured with CES-D score) worsened from 2018/19 to Nov/Dec 2020 for people with mild cognitive impairment (1.39 (95%CI: 1.29-1.49) to 2.16 (2.02-2.30)) or no impairment (1.17 (95%CI: 1.12-1.22) to 2.03 (1.96-2.10)). Anxiety, using a single-item rating of 0-10 also worsened among those with mild cognitive impairment (2.48 (2.30-2.66) to 3.14 (2.95-3.33)) or no impairment (2.20 (2.11-2.28) to 2.85 (2.77-2.95)). No statistically significant increases were found for those with dementia. Using a clinical cutoff for likely depression (CES-D>=4), we found statistically significant increases in the probability of likely clinical depression between 2018/19 and Nov/Dec 2020 for those with no impairment (0.110 (0.099-0.120) to 0.206 (0.191-0.222)) and those with mild impairment (0.139 (0.120-0.159) to 0.234 (0.204-0.263)). We also found that differences according to cognitive function that existed before the pandemic were no longer present by June/July 2020, and there were no statistically significant differences in depression or anxiety among cognitive groups in Nov/Dec 2020. Conclusions: Our findings on measures collected before and during the pandemic suggest a convergence in mental health across cognitive function groups during the pandemic. This suggests mental health services will need to meet an increased demand that will come from older adults, especially those not living with cognitive impairment or dementia. We also found little significant change in mental health outcomes among those with dementia; as their existing need for support will remain, policymakers and care practitioners will need to ensure this group continues to have equitable access to support for their mental health.

Empathy, Fear of Disease and Support for COVID-19 Containment Behaviors: Evidence from 34 Countries on the Moderating Role of Governmental Trust (preprint)

The current study investigated the motives that underlie support for COVID-19 preventive behaviorsin a large, cross-cultural sample of 12,758 individuals from 34 countries. We hypothesized that the associations of empathic prosocial concern and fear of disease, with support towards preventive COVID-19 behaviors would be moderated by the individual-level and country-level trust in the government. Results suggest that the association between fear of disease and support for COVID-19 preventive behaviors was strongest when trust in the government was weak (both at individual and country-level). Conversely, the association with empathic prosocial concern was strongest when trust was high, but this moderation was only found at individual-level scores of governmental trust. We discuss how both fear and empathy motivations to support preventive COVID-19 behaviors may be shaped by socio-cultural context, and outline how the present findings may contribute to a better understanding of collective action during global crises.

Association of Heart Rate Variability with Pulmonary Function Impairment and Symptomatology Post-COVID-19 Hospitalization (preprint)

Persistence of symptoms beyond three months after COVID-19 infection, often referred to as post-COVID-19 condition (PCC), is commonly experienced. It is hypothesized that PCC results from autonomic dysfunction with decreased vagal nerve activity, which can be indexed by low heart rate variability (HRV). The aim of this study was to assess the association of HRV upon admission with pulmonary function impairment and number of reported symptoms beyond three months after initial hospitalization for COVID-19 between February and December 2020. Follow-up took place three to five months after discharge and included pulmonary function tests and the assessment of persistent symptoms. HRV analysis was performed on one 10s electrocardiogram obtained upon admission. Analyses were performed using multivariable and multinomial logistic regression models. Among 171 patients who received follow-up, and with an electrocardiogram at admission, decreased diffusion capacity of the lung for carbon monoxide (DLCO) (41%) was most frequently found. After a median of 119 days (IQR 101-141), 81% of the participants reported at least one symptom. HRV was not associated with pulmonary function impairment or persistent symptoms three to five months after hospitalization for COVID-19.

Promoting Activity, Independence and Stability in early dementia and mild cognitive impairment (PrAISED): A randomised controlled trial (preprint)

Background: Dementia is associated with frailty leading to increased risks of falls and hospitalisations. Interventions are required to maintain functional ability, strength and balance. Design: Multi-centre parallel group randomised controlled trial, with embedded process evaluation. Procedures were adapted during the COVID-19 pandemic. Participants: People with mild dementia or mild cognitive impairment (MCI), living at home, and a family member or carer. Objectives: To determine the effectiveness of an exercise and functional activity therapy intervention compared to usual care. Intervention: A specially-designed dementia-specific rehabilitation programme focussing on strength, balance, physical activity and performance of ADL, which was tailored, progressive, addressed risk and the psychological and learning needs of people with dementia, providing up to 50 therapy sessions over 12 months. The control group received usual care plus a falls risk assessment. Main outcome measure: The primary outcome was the informant-reported Disability Assessment for Dementia (DAD) 12 months after randomisation. Secondary outcomes were: self-reported ADL, cognition, physical activity, quality of life, frailty, balance, functional mobility, fear of falling, mood, carer strain and service use (at 12 months) and falls (between months 4 and 15). Results: 365 people were randomised, 183 to intervention and 182 to control. Median age of participants was 80 years (range 65-95), median Montreal Cognitive Assessment score 20/30 (range 13-26), 58% were men. Participants received a median of 31 (IQR = 22-40) therapy sessions out of a possible maximum of 50. Participants reported completing a mean 121 minutes/week of PrAISED activity outside of supervised sessions. Primary outcome data were available for 149 (intervention) and 141 (control) participants. There was no difference in DAD scores between groups: adjusted mean difference -1.3/100, 95% Confidence Interval (-5.2 to +2.6); Cohens d effect size -0.06 (-0.26 to +0.15); p=0.5. Upper 95% confidence intervals excluded small to moderate effects on any of the range of secondary outcome measures. Between months 4 and 15 there were 79 falls in the intervention group and 200 falls in the control group, adjusted incidence rate ratio 0.78 (0.5 to 1.3); p= 0.3. Conclusion: The intensive PrAISED programme of exercise and functional activity training did not improve ADLs, physical activity, quality of life, reduce falls or improve any other secondary health status outcomes even though uptake was good. Future research should consider alternative approaches to risk reduction and ability maintenance. Trial registration: ISRCTN15320670 . Funding: National Institute for Health and Care Research

Recombinant SARS-CoV-2 Spike Protein and its Receptor Binding Domain stimulate release of different pro-inflammatory mediators via activation of distinct receptors on human microglia cells (preprint)

SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor Angiotensin Converting Enzyme 2 (ACE2) on target cells and results in acute symptoms involving especially the lungs known as COVID-19. However, increasing evidence indicates that SARS-CoV-2 infection produces neuroinflammation associated with neurological, neuropsychiatric, and cognitive symptoms persists well past the resolution of the infection, known as post-COVID-19 sequalae or Long-COVID. The neuroimmune mechanism(s) involved in Long-COVID have not been adequately characterized. In this study, we show that recombinant SARS-CoV-2 full-length S protein stimulates release of pro-inflammatory IL-1b, CXCL8, IL-6 and MMP-9 from cultured human microglia via TLR4 receptor activation. Instead, recombinant receptor-binding domain (RBD) stimulates release of TNF-α, IL-18 and S100B via ACE2 signaling. These results provide evidence that SARS-CoV-2 spike protein contributes to neuroinflammation through different mechanisms that may be involved in CNS pathologies associated with Long-COVID.

The negative impact of COVID-19 on working memory revealed using a rapid online quiz.

Although coronavirus disease 2019 (COVID-19) affects the respiratory system, it can also have neurological consequences leading to cognitive deficits such as memory problems. The aim of our study was to assess the impact of COVID-19 on working memory function. We developed and implemented an online anonymous survey with a working memory quiz incorporating aspects of gamification to engage participants. 5428 participants successfully completed the survey and memory quiz between 8th December 2020 and 5th July 2021 (68.6% non-COVID-19 and 31.4% COVID-19). Most participants (93.3%) completed the survey and memory quiz relatively rapidly (mean time of 8.84 minutes). Categorical regression was used to assess the contribution of COVID status, age, time post-COVID (number of months elapsed since having had COVID), symptoms, ongoing symptoms and gender, followed by non-parametric statistics. A principal component analysis explored the relationship between subjective ratings and objective memory scores. The objective memory scores were significantly correlated with participants' own assessment of their cognitive function. The factors significantly affecting memory scores were COVID status, age, time post-COVID and ongoing symptoms. Our main finding was a significant reduction in memory scores in all COVID groups (self-reported, positive-tested and hospitalized) compared to the non-COVID group. Memory scores for all COVID groups combined were significantly reduced compared to the non-COVID group in every age category 25 years and over, but not for the youngest age category (18-24 years old). We found that memory scores gradually increased over a period of 17 months post-COVID-19. However, those with ongoing COVID-19 symptoms continued to show a reduction in memory scores. Our findings demonstrate that COVID-19 negatively impacts working memory function, but only in adults aged 25 years and over. Moreover, our results suggest that working memory deficits with COVID-19 can recover over time, although impairments may persist in those with ongoing symptoms.

Effectiveness of Non-Face-to-Face Dementia Prevention Program on Cognitive function and Depression in Community-dwelling Elderly during the COVID-19 Pandemic in Korea (preprint)

Background: Continuous participation of dementia prevention program is important to the community-dwelling elderly. Therefore, reducing treatment gaps using non-face-to-face program is important in COVID-19. The aim of this study is to introduce evidence-based non face-to-face dementia prevention program in Korean context, and to identify the effect of non-face-to-face dementia prevention program on cognitive function and depression of community-dwelling elderly during the COVID 19 pandemic. Methods: A total of 101 community-dwelling elderly without dementia participated in 12 sessions of a non-face-to-face dementia prevention program designed by occupational therapist. Cognitive functions and depression were tested. Results: Every item of cognitive function was maintained, and memory increased. The symptoms of depression decreased significantly. From the opinions of the participants, participation in new activities, reduction of boredom, communication, and reminisce were benefits of this program. Conclusions: Non-face-to-face dementia prevention program is an effective method to maintain and increase cognitive function and prevent depression on community-dwelling elderly. The community-based non-face-to-face occupational therapy program of this study is useful to give chance to participate in continuous activities during the COVID 19 pandemic.