Navigating the Landscape of Hint Generation Research: From the Past to the Future (preprint)

Digital education has gained popularity in the last decade, especially after the COVID-19 pandemic. With the improving capabilities of large language models to reason and communicate with users, envisioning intelligent tutoring systems (ITSs) that can facilitate self-learning is not very far-fetched. One integral component to fulfill this vision is the ability to give accurate and effective feedback via hints to scaffold the learning process. In this survey article, we present a comprehensive review of prior research on hint generation, aiming to bridge the gap between research in education and cognitive science, and research in AI and Natural Language Processing. Informed by our findings, we propose a formal definition of the hint generation task, and discuss the roadmap of building an effective hint generation system aligned with the formal definition, including open challenges, future directions and ethical considerations.

Similarities between long COVID and cognitive impairment and potential implications; Results from the 2022 BRFSS (preprint)

BackgroundCOVID has been linked to cognitive issues with brain fog a common complaint among adults reporting long COVID (symptoms lasting 3 or more months). ObjectiveTo study similarities and differences between cognitive impairment (CI) (the cognitive disability measure) and long COVID. MethodsUsing 2022 BRFSS data from 50 states and 169,894 respondents in 29 states with COVID vaccine data, respondents with CI and long COVID were compared in unadjusted analysis and logistic regression. Apparent vaccine effectiveness was compared in the 29 states. ResultsPrevalence of long COVID was 7.4% (95% CI 7.3-7.6) and CI was 13.4% (13.2-13.6) with both rates higher among women, ages 18-64 years, Hispanics, American Indians, ever smokers, those with depression, e-cigarette users, and those with more of the co-morbidities of diabetes, asthma, COPD, and obesity. The strong association between long COVID and CI was confirmed. Apparent vaccine effectiveness of 3 or more doses vs <3 was 38% for long COVID and 35% for CI, in both cases reducing rates for 3 or more doses to those comparable to adults with 0 comorbidities and showing dose response gradients. For CI, apparent vaccine effectiveness was similar for respondents with or without long COVID. Logistic regression confirmed most results except the magnitude of vaccine effectiveness on CI was reduced in some models while vaccine effectiveness for long COVID was confirmed. ConclusionsMore research is needed to understand the apparent effectiveness of COVID vaccines on CI but, if confirmed, results could expand the list of non-infectious outcomes for which mRNA vaccines can be effective.

Greater Role of Cognitive Impairment Over Fatigue in Post-COVID-19 Quality of Life: A Post-Hoc Analysis of a Randomized Controlled Trial (preprint)

BackgroundPost COVID-19 Condition (PCC) is a common and debilitating condition with significant reports of fatigue and psychosocial impairment globally. The extent to which cognitive symptoms and fatigue contribute to reduced quality of life in affected individuals remains clear. MethodsThis is a post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial that evaluated the effect of vortioxetine on cognitive function in adults with PCC. The post-hoc analysis herein aimed to determine the overall effect of baseline cognitive function [as measured by the Digit Symbol Substitution Test (DSST)] and baseline fatigue severity [as measured by the Fatigue Severity Scale (FSS)] on baseline health-related quality of life (HRQoL) [as measured by the 5-item World Health Organisation Well-Being Index (WHO-5)]. ResultsA total of 200 participants were enrolled in the primary trial. Due to missing baseline data, our statistical analysis included baseline measures of 147 individuals. Our generalized linear model analysis revealed a significant positive correlation between DSST-measured objective cognitive function and self-reported WHO-5-measured HRQoL ({beta} = 0.069, 95% CI [0.006, 0.131], p = 0.032). In contrast, our analysis revealed a significant negative correlation between FSS and WHO-5 scores ({beta} = -0.016, 95% CI [-0.021, -0.011], p < 0.001). The beta-coefficient ratio ({beta}DSST / {beta}FSS = 0.069 / 0.016) is calculated as 4.313. ConclusionsOverall, we observed that increased cognitive function was associated with increased HRQoL at baseline in adults with PCC. Moreover, we observed that increased severity of fatigue symptoms was associated with decreased HRQoL at baseline in adults with PCC. Furthermore, we observed that an improvement in cognitive function would have a four-fold greater impact on HRQoL than the effect generated by improvement in fatigue.

Interventions for the management of post COVID-19 condition (long COVID): Protocol for a living systematic review & network meta-analysis (preprint)

Background: Up to 15% of survivors of COVID-19 infection experience long-term health effects, including fatigue, myalgia, and impaired cognitive function, termed post COVID-19 condition or long COVID. Several trials that study the benefits and harms of various interventions to manage long COVID have been published and hundreds more are planned or are ongoing. Trustworthy systematic reviews that clarify the benefits and harms of interventions are critical to promote evidence-based practice. Objective To create and maintain a living systematic review and network meta-analysis addressing the benefits and harms of pharmacologic and non-pharmacologic interventions for the treatment and management of long COVID. Methods Eligible trials will randomize adults with long COVID, to pharmacologic or non-pharmacologic interventions, placebo, sham, or usual care. We will identify eligible studies by searches of MEDLINE, EMBASE, CINAHL, PsycInfo, AMED, and CENTRAL, from inception, without language restrictions. Reviewers will work independently and in duplicate to screen search records, collect data from eligible trials, including trial and patient characteristics and outcomes of interest, and assess risk of bias. Our outcomes of interest will include fatigue, pain, post-exertional malaise, changes in education or employment status, cognitive function, mental health, dyspnea, quality of life, patient-reported physical function, recovery, and serious adverse events. For each outcome, when possible, we will perform a frequentist random-effects network meta-analysis. When there are compelling reasons to suspect that certain interventions are only applicable or effective for a subtype of long COVID, we will perform separate network meta-analyses. The GRADE approach will guide our assessment of the certainty of evidence. We will update our living review biannually, upon the publication of a seminal trial, or when new evidence emerges that may change clinical practice. Conclusion This living systematic review and network meta-analysis will provide comprehensive, trustworthy, and up-to-date summaries of the evidence addressing the benefits and harms of interventions for the treatment and management of long COVID. We will make our findings available publicly and work with guideline producing organizations to inform their recommendations.

Tracking Persistent Symptoms in Scotland (TraPSS): A Longitudinal Prospective Cohort Study of COVID-19 Recovery After Mild Acute Infection (preprint)

Background: COVID-19 disease results in disparate responses between individuals and has led to the emergence of Long-COVID, characterized by persistent and cyclical symptomology. To understand the complexity of Long-COVID, the importance of symptom surveillance and prospective longitudinal studies is evident. Methods: A 9-month longitudinal prospective cohort study was conducted within Scotland (n=287), using a mobile app to determine the proportion of recovered individuals, those with persistent symptoms, common symptoms, and associations with gender and age. Results: 3.1% of participants experienced symptoms at month 9, meeting the criteria for Long-COVID, as defined by the NICE terminology. Fatigue, cough, and muscle pain were the most common symptoms at baseline, with fatigue persisting the longest, while symptoms like cough improved rapidly. Older age increased the likelihood of reporting pain and cognitive impairment. Female gender increased the likelihood of headaches and post-exertional malaise (PEM), and increased recovery time from fatigue and PEM. Conclusions: The majority of people fully recover from acute COVID-19, albeit often slowly. Age and gender play a role in symptom burden and recovery rates, emphasizing the need for tailored approaches to Long-COVID management. Further analysis is required to determine the characteristics of the individuals still reporting ongoing symptoms months after initial infection to identify risk factors and potential predictors for the development of Long-COVID.

Accelerated brain age in young to early middle-aged adults after mild to moderate COVID-19 infection (preprint)

Cognitive decline is a common adverse effect of the Coronavirus Disease of 2019 (COVID-19), particularly in the post-acute disease phase. The mechanisms of cognitive impairment after COVID-19 (COGVID) remain unclear, but neuroimaging studies provide evidence of brain changes, many that are associated with aging. Therefore, we calculated Brain Age Gap (BAG), which is the difference between brain age and chronological age, in a cohort of 25 mild to moderate COVID-19 survivors (did not experience breathlessness, pneumonia, or respiratory/organ failure) and 24 non-infected controls (mean age = 30 +/- 8) using magnetic resonance imaging (MRI). BAG was significantly higher in the COVID-19 group (F = 4.22, p = 0.046) by 2.65 years. Additionally, 80% of the COVID-19 group demonstrated an accelerated BAG compared to 13% in the control group (X2 = 20.0, p < 0.001). Accelerated BAG was significantly correlated with lower cognitive function (p < 0.041). Females in the COVID-19 group demonstrated a 99% decreased risk of accelerated BAG compared to males (OR = 0.015, 95% CI: 0.001 to 0.300). There was also a small (1.4%) but significant decrease in risk for accelerated BAG associated with longer time since COVID-19 diagnosis (OR = 0.986, 95% CI: 0.977 to 0.995). Our findings provide a novel biomarker of COGVID and point to accelerated brain aging as a potential mechanism of this adverse effect. Our results also offer further insight regarding gender-related disparities in cognitive morbidity associated with COVID-19.

Exercise Intolerance in Long Covid After 24 Months From Severe Acute Disease: is There Room for Improvement? (preprint)

Introduction: Long COVID is a complex and multisystemic condition, where dyspnea, fatigue, post-exertional malaise, cognitive impairment, decreased functional capacity, and deterioration in quality of life are the most incident clinical features. Few studies have reported cardiopulmonary alterations 24 months after severe COVID-19 infection.  Objective: to evaluate the functional capacity of individuals with persistent symptoms after severe COVID-19 infection compared to control individuals without symptomatic COVID or mild COVID after 24 months.  Methods: This is a case-control study assessing 34 individuals divided into 2 groups (severe COVID-19 with long COVID and a control group consisting of asymptomatic/mild acute COVID-19 with no long COVID) regarding functional capacity by 6-minute walk test (6MWT) associated with gas analysis, spirometry, respiratory muscle strength and quality of life. Results: During the 6MWT, an important lower heart rate (HR) was observed for the COVID group, with greater exertional perception, a significant decrease in the distance covered, and a low value of O2 uptake (V̇O2) and minute ventilation, in addition to very low quality of life scores, especially in aspects of functional capacity and physical limitations.  Conclusion: individuals who have severe COVID-19 and persist with symptoms have low functional capacity, low V̇O2, low HR behavior, and low quality of life. 

Assessing COVID-19 Vaccine Effectiveness in Frail Long-Term Care Facilities Residents in a Middle-Income Country (preprint)

Background: During the COVID-19 pandemic, individuals residing in long-term care facilities (LTCF) are particularly vulnerable to adverse outcomes due to their higher rates of frailty, disabilities, cognitive impairment, dementia, and chronic illnesses. In low and middle-income nations, research on immunizing frail populations is lacking, while most studies on COVID-19 in LTCF come from wealthier nations and may not fully capture the situation in emerging countries.  Methods: We aimed to evaluate the effectiveness of first, second and third COVID-19 vaccine doses, against infections, hospitalizations, and deaths, and their association with frailty, age, sex and chronic disease, among older adults, in a social vulnerability context. This retrospective cohort study, comprises a total of 712 older adults, in a social vulnerability context, of 29 LTCF, in Brazil. Continuous variables were described by medians and interquartile ranges and categorical variables were represented by absolute and relative frequencies. The Mann-Whitney test was used. For evaluating the relation between categorical variables, Pearson's chi-square test was used. When comparing proportions, the Z test of proportion was applied. A significance level of 5% was considered.  Results: Median age was 81.37 years, 72.8% were female, 94.61% were frail, 79.97% had a cognitive impairment, 69.54% had a mobility impairment, 78.37% have, at least, one chronic disease and 72.73% use five or more medications per day. Before the vaccine, mobility impairment was associated with great contamination rates (p=.03); frailty (p=.02) and previous pulmonary disease (p=.03) with symptoms of gravity; frailty (p=.02), pulmonary disease (p=.04) and male sex (p=.02) with emergency care or hospital admission. After the third vaccine dose, only frailty remains associated with admissions (p=.03). The number of positive cases (p=.001), symptomatic patients (p<.001), admissions (p=.001) and deaths (p<.001) were substantially reduced after the three vaccine doses.  Conclusions and Implications: Even in a frail population, the vaccine was effective, in the reduction of positive cases, the number of symptomatic patients, admission to emergency or hospital care and deaths. Before the vaccine, frailty, previous pulmonary disease and male sex were associated with worse outcomes. After the vaccine, frailty remains associated with a major number of admissions.

Co-ultraPEALut in Subjective Cognitive Impairment Following SARS-CoV-2 Infection: An Exploratory Retrospective Study (preprint)

Neurological involvement following COronaVIrus Disease 19 (COVID-19) is thought to have a neuroinflammatory etiology. Co-ultraPEALut (an antiinflammatory molecule) and luteolin (an antioxidant) yielded promising results as neuroinflammation antagonists. This study aimed at describing cognitive impairment in post-COVID patient treated with co-ultraPEALut. Montreal Cognitive Assessment (MoCA), Prospective-Retrospective Memory Questionnaire (PRMQ), Fatigue Severity Scale (FSS) and a subjective evaluation were administered at baseline and after 10 months. Co-ultraPEALut-treated patients were retrospectively compared with controls. 26 co-ultraPEALut-treated patients showed significant improvement in PRMQ (T0: 51.94±10.55, T1: 39.67±13.02, p

Syndromic case definitions for Lower Respiratory Tract Infection (LRTI) are less sensitive in older age: an analysis of symptoms among hospitalised adults (preprint)

Background Lower Respiratory Tract Infections (LRTI) pose a serious threat to older adults but may be underdiagnosed due to atypical presentations. Here we assess LRTI symptom profiles and syndromic (symptom-based) case ascertainment in older (≥65y) as compared to younger adults (<65y). Methods We included adults (≥18y) with confirmed LRTI admitted to two acute care Trusts in Bristol, UK from 1st August 2020- 31st July 2022.  Logistic regression was used to assess whether age ≥65y reduced the probability of meeting syndromic LRTI case definitions, using patients’ symptoms at admission. We also calculated relative symptom frequencies (log-odds ratios) and evaluated how symptoms were clustered across different age groups. Results Of 17,620 clinically confirmed LRTI cases, 8,487 (48.1%) had symptoms meeting the case definition. Compared to those not meeting the definition these cases were younger, had less severe illness and were less likely to have received a SARS-CoV-2 vaccination or to have active SARS-CoV-2 infection. Prevalence of dementia/cognitive impairment and levels of comorbidity were lower in this group. After controlling for sex, dementia and comorbidities, age ≥65y significantly reduced the probability of meeting the case definition (aOR=0.67, 95% CI:0.63-0.71). Cases aged ≥65y were less likely to present with fever and LRTI-specific symptoms (e.g., pleurisy, sputum) than younger cases, and those aged ≥85y were characterised by lack of cough but frequent confusion and falls. Conclusions LRTI symptom profiles changed considerably with age in this hospitalised cohort. Standard screening protocols may fail to detect older and frailer cases of LRTI based on their symptoms.

Coronavirus Disease 2019 and its Impact on the Cognition of Older Adults: Unraveling the Role of Inflammation (preprint)

Background: The Coronavirus Disease 2019 (COVID-19) pandemic has had a significant global impact, particularly on the older adult population. To address concerns regarding the emergence and persistence of cognitive impairment and its potential risk factors, this study aimed to investigate cognitive function and its relationship with inflammation in older COVID-19 survivors during a three-month follow-up. Methods: In this descriptive-analytical study, 177 hospitalized patients with COVID-19 aged >60 years were examined between July 2021 and February 2022.Psychiatric and cognitive assessments were conducted at discharge and at one month and three months post-discharge. All the statistical analyses were conducted using a Statistical Package for the Social Sciences (SPSS) version 24 (P<0.05). Cognitive status was analyzed with the Repeated Measures Test, and relationships between inflammatory indices and cognitive function were explored via the Pearson correlation test and Mann‒Whitney U test. The normality of the data was examined using the Kolmogorov‒Smirnov test. Results:A cognitive assessment of patients indicated lower scores onthe informant subscales of the General Practitioner Assessment of Cognition (GPCOG) during the time of discharge, as well as at the 1-and 3-month follow-up intervals. Negative correlations were found between cognitive function and depression/anxiety. Elevated C-reactive protein (CRP), D-dimer, and Lactate dehydrogenase (LDH) levels were linked to lower cognitive scores, while the Erythrocyte sedimentation rate (ESR) and Creatine phosphokinase (CPK) were not significantly correlated. Over time, cognitive function and anxiety improved, while depression and daily activity challenges persisted. Conclusions: This study highlights the lingering impact of inflammation on cognition among older COVID-19 survivors. Moreover, these findings underscore the urgent need for focused interventions and rehabilitation efforts to foster sustained cognitive recovery in this population.

Repeated Hand Grip Strength is an Objective Marker for Disability and Severity of Key Symptoms in Post-COVID ME/CFS (preprint)

Post-COVID Syndrome (PCS) refers to a diverse array of symptoms that persist beyond 3 months of the acute phase of a SARS-CoV-2 infection. The most frequent symptom is fatigue, which can manifest both mentally and physically. In this study, handgrip strength (HGS) parameters were determined as an objective measure of muscle fatigue and fatigability. HGS parameters were correlated with other fre-quent symptoms among 144 female PCS patients suffering from fatigue, exertional intolerance, and cognitive impairment. Seventy-eight patients met the Canadian Consensus Criteria (CCC) for post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The severity of disa-bility and key symptoms were evaluated utilizing self-reported questionnaires. Notably, patients di-agnosed with ME/CFS exhibited a higher overall severity of symptoms, including lower physical func-tion (p < 0.001), a greater degree of disability (p < 0.001), more severe fatigue (p < 0.001), post-exertional malaise (p < 0.001), and autonomic dysfunction (p = 0.004). While HGS was similarly impaired in both PCS and ME/CFS patients, the associations between HGS and the severity of symptoms and disability revealed striking differences. We observed significant correlations of HGS parameters with physical function across all patients, but with the key symptoms PEM, fatigue, cog-nitive impairment, and autonomic dysfunction in ME/CFS patients only. This points to a common mechanism for these symptoms in the ME/CFS subtype, distinct from that in other types of PCS. Further HGS provides an objective marker of disease severity in ME/CFS.

Effect of Paxlovid Treatment on Long COVID Onset: An EHR-Based Target Trial Emulation from N3C (preprint)

Preventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. In this study, we examined whether treatment with Paxlovid in the acute phase of COVID-19 helps prevent the onset of PASC. We used electronic health records from the National Covid Cohort Collaborative (N3C) to define a cohort of 426,461 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation (TTE) framework to estimate the effect of Paxlovid treatment on PASC incidence. Our primary outcome measure was a PASC computable phenotype. Secondary outcomes were the onset of novel cognitive, fatigue, and respiratory symptoms in the post-acute period. Paxlovid treatment did not have a significant effect on overall PASC incidence (relative risk [RR] = 0.99, 95% confidence interval [CI] 0.96-1.01). However, its effect varied across the cognitive (RR = 0.85, 95% CI 0.79-0.90), fatigue (RR = 0.93, 95% CI 0.89-0.96), and respiratory (RR = 0.99, 95% CI 0.95-1.02) symptom clusters, suggesting that Paxlovid treatment may help prevent post-acute cognitive and fatigue symptoms more than others.

How executive control and emotional reactivity influence coping strategies in psychiatric patients during the COVID-19 pandemic (preprint)

BackgroundDuring times of environmental challenges, adaptive coping strategies are essential to maintain mental health. Coping relies on executive control, which is often impaired in individuals with psychiatric disorders. Furthermore, emotional reactivity may interfere with executive control. Studying the association between cognitive skills and adaptive coping strategies, as well as the potential impact of emotional reactivity, could inform how we can provide mental support during large-scale adversity. In this study we examined coping strategies in a thoroughly phenotyped psychiatric cohort, the MIND-Set cohort, during the early COVID-19 pandemic stage. MethodsWe studied 1) the association between coping and both subjective and objective executive control before the pandemic, and three different coping strategies used during the pandemic, 2) the mediating role of emotional reactivity, indexed by amygdala reactivity, and 3) the moderating role of the presence of a psychiatric diagnosis in these associations. After finding no specific impact of patient or control status in this association, we decided to post-hoc study the transdiagnostic impact of depression severity in these associations. Resultsshowed 1) only a significant association between subjective executive control and a self-reported positive reappraisal style and corona-related reappraisal. However, after controlling for depression severity, this association was no longer significant. Additionally, objective executive control was only directly associated with right amygdala reactivity, while amygdala reactivity in neither of the hemispheres mediated the association between executive control and any of the coping styles. Furthermore, the type of diagnosis did not moderate the association between executive control and coping. ConclusionOur findings firstly underline the difference between self-reported and performance based executive control. While both deficits in subjective and performance based EC may play a role in the persistence of psychiatric symptomatology, this finding emphasizes how depressive symptoms or negative affect can impact reappraisal ability. As this ability is fundamental to staying resilient, treatments focused on reducing negative affect and thereby training reappraisal are pivotal in the maintenance of mental health in the entire population during environmental challenges. Competing Interest StatementThe authors have declared no competing interest.

A Murine Model of Post-acute Neurological Sequelae Following SARS-CoV-2 Variant Infection (preprint)

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies against Delta and Omicron variants in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients and may be useful for future assessment of the efficacy of vaccines and therapeutics against SARS-CoV-2 variants.

Antigen non-specific CD8+ T cells accelerate cognitive decline in aged mice following respiratory coronavirus infection (preprint)

Primarily a respiratory infection, numerous patients infected with SARS-CoV-2 present with neurologic symptoms, some continuing long after viral clearance as a persistent symptomatic phase termed "long COVID". Advanced age increases the risk of severe disease, as well as incidence of long COVID. We hypothesized that perturbations in the aged immune response predispose elderly individuals to severe coronavirus infection and post-infectious sequelae. Using a murine model of respiratory coronavirus, mouse hepatitis virus strain A59 (MHV-A59), we found that aging increased clinical illness and lethality to MHV infection, with aged animals harboring increased virus in the brain during acute infection. This was coupled with an unexpected increase in activated CD8+ T cells within the brains of aged animals but reduced antigen specificity of those CD8+ T cells. Aged animals demonstrated spatial learning impairment following MHV infection, which correlated with increased neuronal cell death and reduced neuronal regeneration in aged hippocampus. Using primary cell culture, we demonstrated that activated CD8+ T cells induce neuronal death, independent of antigen-specificity. Specifically, higher levels of CD8+ T cell-derived IFN-{gamma} correlated with neuronal death. These results support the evidence that CD8+ T cells in the brain directly contribute to cognitive dysfunction following coronavirus infection in aged individuals. eTOC summaryUsing a murine model of respiratory coronavirus infection, we show that aging amplifies post-infectious cognitive dysfunction due to activated CD8+ T cells that secrete IFN-{gamma} in the brain. These data provide evidence that CD8+ T cells in the brain negatively impact post-infectious cognitive function.

Neurocognitive Changes in Patients with Post-COVID Depression (preprint)

Depression and cognitive impairment are recognized complications of COVID-19. This study aimed to assess cognitive performance in clinically diagnosed post-COVID depression (PCD) patients using neuropsychological testing. The study involved 71 post-COVID patients, with matched control groups: recovered COVID-19 individuals without complications (n=18) and individuals without prior COVID-19 history (n=19). A post-COVID depression group (PCD, n=25) was identified based on psychiatric diagnosis, a comparison group (noPCD, n=46) included participants with neurological COVID-19 complications, excluding clinical depression. The PCD patients showed significantly less scores in the MoCA test, decreased immediate memory recall in the Word Memory Test, decreased processing speed and higher accuracy in the Trail Making Test, and near to significant worse executive control and processing speed in the Stroop task compared to controls and the noPCD patients. The number of post-COVID symptoms negatively correlated with immediate word memory recall and processing speed among all post-COVID patients. In PCD patients, negative correlations between number of post-COVID symptoms and delayed recall, between time after recovery and immediate recall, and positive correlation between the number of acute symptoms and processing speed in the incongruent condition of the Stroop task were found. No differences between groups in Sniffin’s stick olfactory test was found. Overall, our study revealed cognitive impairment in PCD patients similar to those in major depressive disorder.

Olfactory and Cognitive Decrements in 1991 Gulf War Veterans (preprint)

Background Prominent symptoms of Gulf War illness (GWI), the disorder related to military service in the 1991 Gulf War (GW), include fatigue, pain, and cognitive dysfunction. Although anosmia is not a typical GWI symptom, anecdotally some veterans reported losing their sense smell shortly after the war. Because olfactory deficit is a prodromal symptom of neurodegenerative diseases like Parkinson’s and Alzheimer’s disease, and because we previously reported suggestive evidence that deployed GW veterans may be at increased risk for Mild Cognitive Impairment (MCI) and dementia, the current study examined the relationship between olfactory and cognitive function in deployed GW veterans.Methods Eighty deployed GW veterans (mean age: 59.9 ± 7.0; 4 female) were tested remotely with the University of Pennsylvania Smell Identification Test (UPSIT) and the Montreal Cognitive Assessment (MoCA). Veterans also completed self-report questionnaires about their health and deployment-related exposures and experiences. UPSIT and MoCA data from age-matched healthy controls (HC) were downloaded from the Parkinson’s Progression Markers Initiative (PPMI) study for comparison.Results GW veterans had a mean UPSIT score of 27.8 ± 6.3 (range 9–37) and a mean MoCA score of 25.3 ± 2.8 (range 19–30). According to age- and sex-specific normative data, 31% of GW veterans (vs. 8% PPMI HCs) had UPSIT scores below the 10th percentile. Nearly half (45%) of GW veterans (vs. 8% PPMI HCs) had MoCA scores below the cut-off for identifying MCI. Among GW veterans, but not PPMI HCs, there was a positive correlation between UPSIT and MoCA scores (Spearman’s ρ = 0.39, p < 0.001). There was no significant difference in UPSIT or MoCA scores between GW veterans with and without history of COVID and with and without Kansas GWI exclusionary conditions.Conclusions We found evidence of olfactory and cognitive deficits and a significant correlation between UPSIT and MoCA scores in a cohort of 80 deployed GW veterans. Because impaired olfactory function has been associated with increased risk for MCI and dementia, it may be prudent to screen aging, deployed GW veterans with smell identification tests so that hypo- and anosmic veterans can be followed longitudinally and offered targeted neuroprotective therapies as they become available.

Lingering symptoms in non-hospitalized patients with COVID-19 – a prospective survey study of symptom expression and effects on mental health in Germany (preprint)

Background The infection rates with SARS-CoV 2 virus, known since 2019, are currently significantly weakened in their dynamics. Nevertheless, COVID 19 is still a common disease, which in most cases is overcome quite well and can be treated by the general practitioner. Despite an initially uncomplicated disease progression, the long-term consequences can be considerable. Symptoms persisting over a period of more than 12 weeks after infection are summarized as Post-COVID (PC) syndrome. The aim of this study is to document the symptom expression in PC patients in the outpatient setting, with a major focus on limitations in daily life and consequences for mental health.Methods This survey is part of a prospective European collaborative study with the German cohort having been slightly extended and evaluated separately. Data collection was performed by telephone interviews of adult SARS CoV 2 positive patients using standardized questionnaires (38 open and 6 closed questions). After an inclusion interview, follow-up interviews were conducted every 4 weeks over a period of 6 months. Participants were recruited in collaboration with the local health department (Würzburg, Germany).Results Sixty participants were recruited in April and May 2021. After 12 weeks (PC cutoff), 48% still reported symptoms related to SARS-CoV-2 infection. The most commonly reported symptoms were fatigue (33%), cognitive impairment (27%), and breathing problems (23%). One-quarter of respondents reported impaired functioning, with the most common daily limitations being sports (28%), work (25%), and social life (15%). At 6 months, 22% of respondents experienced anxiety and 12% reported depressive symptoms. Overall, 40% of respondents were concerned that their health would deteriorate again or not fully normalize because of COVID-19. Over two-thirds (70%) visited a physician during the course of the study because of COVID-19, 74% of whom visited their general practitioner.Conclusion PC in the outpatient setting is a common, difficult and multidimensional condition. In addition to physical symptoms, limitations in mental health and activities of daily life are particularly apparent. PC is not yet fully understood in its complexity and poses long-term challenges, particularly for outpatient care. Routine screening for psychosocial comorbidities can help to offer supportive measures to prevent chronification and/or somatization.

Long COVID is associated with severe cognitive slowing (preprint)

Background COVID-19 survivors may suffer from a wide range of chronic cognitive symptoms for months or years as part of post-COVID-19 conditions (PCC). To date, there is no definitive objective cognitive marker for PCC. We hypothesised that a key common deficit in people with PCC might be generalised cognitive slowing. Methods To examine cognitive slowing, PCC patients completed two short web-based cognitive tasks, Simple Reaction Time (SRT) and Number Vigilance Test (NVT). 270 patients diagnosed with PCC at two different clinics in UK and Germany were compared to two control groups: individuals who contracted COVID-19 before but did not experience PCC after recovery (No-PCC group) and uninfected individuals (No-COVID group). Findings We identified pronounced cognitive slowing in PCC patients, which distinguished them from age-matched healthy individuals who previously had symptomatic COVID-19 but did not manifest PCC. Cognitive slowing was evident even on a 30-second task measuring simple reaction time (SRT), with PCC patients responding to stimuli ~3 standard deviations slower than healthy controls. This finding was replicated across two clinic samples in Germany and the UK. Comorbidities such as fatigue, depression, anxiety, sleep disturbance, and post-traumatic stress disorder did not account for the extent of cognitive slowing in PCC patients. Furthermore, cognitive slowing on the SRT was highly correlated with the poor performance of PCC patients on the NVT measure of sustained attention. Interpretation Together, these results robustly demonstrate pronounced cognitive slowing in people with PCC, which distinguishes them from age-matched healthy individuals who previously had symptomatic COVID-19 but did not manifest PCC. This might be an important factor contributing to some of the cognitive impairments reported in PCC patients. Funding Wellcome Trust (206330/Z/17/Z), NIHR Oxford Health Biomedical Research Centre, the Thuringer Aufbaubank (2021 FGI 0060), German Forschungsgemeinschaft (DFG, FI 1424/2-1) and the Horizon 2020 Framework Programme of the European Union (ITN SmartAge, H2020-MSCA-ITN-2019-859890).