Association between previous SARs-CoV-2 infection and new prescription of antidepressant drugs: a case-control study in Friuli Venezia Giulia region, Italy.

PURPOSE: A rise in affective and anxiety disorders and in antidepressant (AD) treatment during the COVID-19 pandemic has been extensively described, but few studies were provided at the individual level, further considering COVID-19 severity and vaccination status. METHODS: Case-control study evaluating the association between the new use of ADs and a previous COVID-19 infection, in Friuli Venezia Giulia Region, Italy, from March 1, 2020, to July 19, 2022. Multiple conditional logistic regressions assess the association between a new AD use and a COVID-19 infection previous to the index date, stratified by gender, age and anti-COVID-19 vaccination status. Odds Ratios (OR) and 95% confidence intervals were reported. RESULTS: COVID-19 was associated with AD treatment after the infection. The disease severity was positively associated with a growing risk of being dispensed an AD, with the highest risk in unvaccinated subjects previously hospitalised in ICU (OR = 28.77). The risk of using ADs after COVID-19 infection was higher in unvaccinated subjects aged 65 years and older, both females and males. The association between COVID-19 infection and AD dispensation in vaccinated subjects was not significant, with the exception of females aged 65 years and over. CONCLUSIONS: Anti-COVID-19 vaccination, especially among the elderly, might prevent post-COVID AD treatment. Clinicians should be aware that COVID-19 patients requiring hospitalisation are more likely to experience these symptoms, given their higher risk of being dispensed ADs. Future studies may benefit by analysing the incidence of both mental disorders and psychotropic treatment in post-COVID patients, considering socioeconomic factors and vaccination status.

Relationship between anhedonia and psychosocial functioning in post-COVID-19 condition: a post-hoc analysis.

BACKGROUND: Post-COVID-19 condition (PCC), also known as "long COVID," is characterized by persistent symptoms, negatively affecting the well-being of individuals with PCC. Anhedonia (i.e. reduced capacity for pleasure) and compromised psychosocial functioning are notable symptoms in those with PCC. We aimed to provide insights to understand the effects of anhedonia and impaired psychosocial functioning of individuals with PCC. METHODS: This post-hoc analysis used data from an 8-week, double-blind, randomized, placebo-controlled trial which evaluated vortioxetine for cognitive deficits in individuals with PCC (Clinicaltrials.gov Identifier: NCT05047952). A total of 147 eligible participants were randomly assigned to receive vortioxetine or matching placebo over eight weeks of double-blind treatment. Our study investigated the relationship between anhedonia, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS), and psychosocial functioning, measured with the Post-COVID Functional Status (PCFS) scale. The analysis was conducted using a generalized linear model, with adjustments for relevant covariates such as age, sex, education, suspected versus confirmed COVID diagnosis, MDD diagnosis, and alcohol consumption. RESULTS: Of the 147 participants, 143 participants had available baseline data for analysis. We observed that baseline PCFS score was statistically significantly positively correlated to baseline SHAPS score (ß = 0.070, p = 0.045, 95% CI). DISCUSSIONS: Our analysis revealed a significant relationship between measures of anhedonia and psychosocial functioning in adults with PCC. Strategies that aim to improve patient-reported outcomes with PCC need to prioritize the prevention and treatment of hedonic disturbances in patients experiencing PCC.

Illness presentation and quality of life in myalgic encephalomyelitis/chronic fatigue syndrome and post COVID-19 condition: a pilot Australian cross-sectional study.

PURPOSE: Post COVID-19 Condition (PCC), being persistent COVID-19 symptoms, is reminiscent of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)-a chronic multi-systemic illness characterised by neurocognitive, autonomic, endocrinological and immunological disturbances. This novel cross-sectional investigation aims to: (1) compare symptoms among people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) to inform developing PCC diagnostic criteria; and (2) compare health outcomes between patients and people without acute or chronic illness (controls) to highlight the illness burdens of ME/CFS and PCC. METHODS: Sociodemographic and health outcome data were collected from n = 61 pwME/CFS, n = 31 pwPCC and n = 54 controls via validated, self-administered questionnaires, including the 36-Item Short-Form Health Survey version 2 (SF-36v2) and World Health Organization Disability Assessment Schedule version 2.0 (WHODAS 2.0). PwME/CFS and pwPCC also provided self-reported severity and frequency of symptoms derived from the Canadian and International Consensus Criteria for ME/CFS and the World Health Organization case definition for PCC. RESULTS: Both illness cohorts similarly experienced key ME/CFS symptoms. Few differences in symptoms were observed, with memory disturbances, muscle weakness, lymphadenopathy and nausea more prevalent, light-headedness more severe, unrefreshed sleep more frequent, and heart palpitations less frequent among pwME/CFS (all p < 0.05). The ME/CFS and PCC participants' SF-36v2 or WHODAS 2.0 scores were comparable (all p > 0.05); however, both cohorts returned significantly lower scores in all SF-36v2 and WHODAS 2.0 domains when compared with controls (all p < 0.001). CONCLUSION: This Australian-first investigation demonstrates the congruent and debilitating nature of ME/CFS and PCC, thereby emphasising the need for multidisciplinary care to maximise patient health outcomes.

Lower hair cortisol concentration in adolescent and young adult patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Q-Fever Fatigue Syndrome compared to controls.

BACKGROUND: In patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), momentary cortisol concentrations in blood, urine, and saliva are lower compared to healthy controls. Long-term cortisol concentration can be assessed through hair, but it is unclear whether these concentrations are also lower. Additionally, it is unknown if lower cortisol extends to other patients suffering from persistent fatigue and how hair cortisol concentration (HCC) relates to fatigue levels. Therefore, this study examines HCC in fatigued patients with ME/CFS, Q fever Fatigue Syndrome (QFS), Post-COVID-19 condition (PCC), and Juvenile Idiopathic Arthritis (JIA). METHODS: Adolescent and young adult patients with ME/CFS (n=12), QFS (n=20), PCC (n=8), JIA (n=19), and controls (n=57) were included. Patients participated in a randomized cross-over trial (RCT) targeting fatigue through lifestyle and dietary self-management strategies. HCC was measured pre-post RCT in patients and once in controls, quantified using a LC-MS/MS-based method. Fatigue severity was measured with the Checklist Individual Strength-8. HCC was compared between groups with ANOVAs. Relations between HCC, fatigue severity, and other variables were investigated using linear regression analyses. RESULTS: The ME/CFS (p=.009) and QFS (p=.047) groups had lower HCC compared to controls. Overall, HCC was negatively associated with the presence of symptoms related to chronic fatigue syndromes (e.g., sleeping issues, often feeling tired, trouble thinking clearly; ß=-0.018, p=.035), except in the QFS group (ß=.063, p<.001). Baseline HCC did not predict fatigue improvement during the RCT (p=.449), and HCC increased during the trial (Mdif=.076, p=.021) regardless of clinically relevant fatigue improvement (p=.658). CONCLUSION: Lower cortisol concentration can also be observed in the long-term. Lower HCC is not limited to ME/CFS, as it was also observed in QFS. The role of cortisol may differ between these diagnoses and appears to be unrelated to fatigue levels.

Reliability and Validity of the Japanese Version of the Fatigue Assessment Scale.

Objective General fatigue is one of the most frequent chief complaints in primary care, and an accurate assessment of fatigue has a direct impact on a patient's quality of life and treatment decisions. The Fatigue Assessment Scale (FAS), a measure of general fatigue, is useful for assessing fatigue in diverse cultures and diseases. However, there has been no study showing the reliability and validity of the scale in the Japanese context. The present study assessed the reliability and validity of the Japanese version of the FAS. Methods This study was conducted on 649 patients with long COVID who had a high frequency of general fatigue. To test the structural validity of the FAS, the patients were randomly divided into two groups: one in which an exploratory factor analysis (EFA) was conducted and one in which a confirmatory factor analysis (CFA) was conducted. Cronbach's alpha was calculated to assess internal consistency reliability. Results As 58 patients had missing values, we analyzed the data of 591 patients. The EFA led to an FAS comprising two factors. The CFA showed an acceptable fit for this two-factor model. The internal consistency was found to be good (Cronbach's alpha =0.89). Conclusion This study verified the structural validity and internal consistency and reliability of the Japanese version of the FAS. The results indicate that the Japanese version of the FAS is useful for assessing general fatigue in patients with long COVID in Japan.

Prevention of post COVID-19 condition by early treatment with ensitrelvir in the phase 3 SCORPIO-SR trial.

This exploratory analysis of the double-blind, phase 3, SCORPIO-SR trial assessed the effect of ensitrelvir in preventing post coronavirus disease 2019 (COVID-19) condition (PCC). Patients with mild-to-moderate COVID-19 were randomized (1:1:1) within 120 h of symptom onset; received 5-day oral ensitrelvir 125 mg (375 mg on day 1), 250 mg (750 mg on day 1), or a matching placebo once daily; and were assessed for the severity of typical PCC symptoms using a self-administered questionnaire. In total, 341, 317, and 333 patients were assessed in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively (mean age, 35.6-36.5 years; men, 53.3%-58.3%). On days 85, 169, and 337, ensitrelvir 125-mg treatment showed 32.7% (95% confidence interval [CI]: 30.6, 66.1), 21.5% (95% CI: 37.3, 55.6), and 24.6% (95% CI: 43.7, 60.9) reductions versus placebo, respectively, in the risk of any of the 14 acute-phase COVID-19 symptoms (at least one mild, moderate, or severe symptom with general health not returning to the usual level). Ensitrelvir 250-mg treatment showed 10.9% (95% CI: 67.0, 52.8), 9.5% (95% CI: 56.6, 48.0), and 30.6% (95% CI: 36.2, 65.5) risk reductions versus placebo on days 85, 169, and 337, respectively. Risk reductions were observed in any of the 4 neurological symptoms and were more pronounced among patients with high acute-phase symptom scores at baseline and among those with a baseline body mass index ≥25 kg/m2. Ensitrelvir treatment in the acute phase of COVID-19 may reduce the risk of various symptoms associated with PCC. TRIAL REGISTRATION NUMBER: jRCT2031210350.

Changes in Working Situations of Employed Long COVID Patients: Retrospective Study in Japanese Outpatient Clinic.

Purpose: The present study aimed to uncover the impact of long COVID on the working situations of Japanese patients. Methods: Changes in the working situations of the patients who visited our long COVID clinic were evaluated from medical records for the aspects of physical status, quality of life (QOL), and mental conditions. Results: Of 846 long COVID patients who visited our clinic from February 2021 to December 2023, 545 employed patients aged between 18 and 65 years were included in this study. A total of 295 patients (54.1%) with long COVID (median age: 43 years, female: 55.6%) experienced changes in their working status. Those patients included 220 patients (40.4%) who took a leave of absence, 53 patients (9.7%) who retired, and 22 patients (4%) with reduced working hours. Most of the patients (93.2%) with changes in working conditions had mild disease severity in the acute phase of COVID-19. The majority of those patients with mild disease severity (58.8%) were infected in the Omicron-variant phase and included 65.3% of the female patients. The major symptoms in long COVID patients who had changes in their working situations were fatigue, insomnia, headache, and dyspnea. Scores indicating fatigue and QOL were worsened in long COVID patients who had changes in their working situations. In addition, 63.7% of the long COVID patients with changes in their working situations had decreases in their incomes. Conclusions: Changes in the working situation of long COVID patients who were employed had a negative impact on the maintenance of their QOL.

Effectiveness of molnupiravir for treating COVID-19 in patients with psychiatric disorders.

Objectives: This study investigated the clinical effectiveness of molnupiravir for treating non-hospitalized COVID-19 patients with pre-existing psychiatric disorder. Methods: This retrospective cohort study used the TriNetX research network to identify patients with psychiatric disorder who experienced non-hospitalized COVID-19 between 1 January 2022, and 1 May 2023. The propensity score matching (PSM) method was used to match patients receiving molnupiravir (treated group) with those who did not (untreated group). The outcome included short-term outcomes - the composite of all-cause hospitalization or death within 30 days and the risk of post-COVID-19 conditions up to a year after COVID-19 diagnosis. Results: Two groups of 9,421 patients, each with balanced baseline characteristics, were identified using the PSM method. During the 30-day follow-up, treated group was associated with a reduced risk of hospitalization or mortality compared to untreated group (HR, 0.760; 95% CI, 0.665-0.869). Compared to untreated group, treated group also exhibited a decreased risk of experiencing post-COVID-19 conditions, including chest/throat pain (HR, 0.615; 95% CI, 0.543-0.696), abnormal breathing (HR, 0.761; 95% CI, 0.687-0.884), abdominal symptoms (HR, 0.748; 95% CI, 0.674-0.831), fatigue (HR, 0.718; 95% CI, 0.638-0.808), headache (HR, 0.753; 95% CI, 0.665-0.852), cognitive symptoms (HR, 0.769; 95% CI, 0.630-0.940), myalgia (HR, 0.647; 95% CI, 0.530-0.789), cough (HR, 0.867; 95% CI, 0.770-0.978), and palpitation (HR, 0.641; 95% CI, 0.534-0.770) during the 1-year follow-up. Conclusion: Molnupiravir could be associated with lower rates of all-cause hospitalization or death and also lower risk of post-COVID-19 condition among non-hospitalized COVID-19 patients with pre-existing psychiatric disorder.

Post-Acute Sequelae of SARS-CoV-2 Infection and Its Impact on Adolescents and Young Adults.

This review discusses the varying definitions for post-acute sequelae of SARS CoV-2 infection (PASC) in adolescents and young adults (AYAs), symptom profiles of AYAs with PASC, and assessment and management strategies when AYAs present with symptoms concerning for PASC. Additionally, it reviews the impact that PASC can have on AYAs and includes strategies for providers to support AYAs with PASC. Finally, it concludes with a discussion around equity in the care of AYAs with possible PASC.

Effectiveness of pulmonary rehabilitation programmes and/or respiratory muscle training in patients with post-COVID conditions: a systematic review.

BACKGROUND: The term "post-COVID-19 condition" refers to the symptomatology that appears between four to twelve weeks after Covid-19 infection. These symptoms can persist for weeks or even months, significantly diminishing the quality of life for affected individuals. The primary objective of this study was to assess the effectiveness of pulmonary rehabilitation programs and/or respiratory muscle training on respiratory sequelae in patients with post-COVID condition. METHODS: The literature search was conducted in the following databases: PubMed, PEDro, Embase, Cochrane, Scopus, and Web of Science. Randomized clinical trials were included in which participants were aged 18 years or older. Articles were excluded if at least one of the therapies did not involve pulmonary rehabilitation or respiratory muscle training, if the participants were COVID positive, if studies lacked results, and finally, if interventions were conducted without supervision or at home. This review only encompasses supervised non-virtual interventions. This study adheres to the PRISMA statement and has been registered in the PROSPERO database (CRD42023433843). RESULTS: The outcomes obtained in the included studies are assessed across the following variables: Exercise capacity using the 6-minute walk test, Dyspnea, fatigue, Pulmonary function, Maximum inspiratory pressure, and Quality of life. CONCLUSION: Despite the absence of a specific treatment at present, it was evident from this review that a well-structured pulmonary rehabilitation program that incorporates both aerobic and muscular strength exercises along with techniques and inspiratory muscle exercises was the most effective form of treatment.

Post-COVID-19 condition: a sex-based analysis of clinical and laboratory trends.

Background and aim: Post-COVID-19 condition (PCC) encompasses long-lasting symptoms in individuals with COVID-19 and is estimated to affect between 31-67% of patients, with women being more commonly affected. No definitive biomarkers have emerged in the acute stage that can help predict the onset of PCC, therefore we aimed at describing sex-disaggregated data of PCC patients from a local cohort and explore potential acute predictors of PCC and neurologic PCC. Methods: A local cohort of consecutive patients admitted with COVID-19 diagnosis between June 2020 and July 2021 were registered, and clinical and laboratory data were recorded. Only those <65 years, discharged alive and followed up at 6 and 12 months after admission were considered in these analyses. Multivariable logistic regression analysis was performed to explore variables associated with PCC (STATA v 18.0). Results: From 130 patients in the cohort, 104 were contacted: 30% were women, median age of 42 years. At 6 months, 71 (68%) reported PCC symptoms. Women exhibited a higher prevalence of any PCC symptom (87 vs. 60%, p = 0.007), lower ferritin (p = 0.001) and procalcitonin (p = 0.021) and higher TNF levels (p = 0.042) in the acute phase compared to men. Being women was independently associated to 7.60 (95% CI 1.27-45.18, p = 0.026) higher risk for PCC. Moreover, women had lower return to normal activities 6 and 12 months. Conclusion: Our findings highlight the lasting impact of COVID-19, particularly in young women, emphasising the need for tailored post-COVID care. The lower ferritin levels in women are an intriguing observation, warranting further research. The study argues for comprehensive strategies that address sex-specific challenges in recovery from COVID-19.

Challenging the current hypothesis that thrombosis is responsible for the post-COVID-19 condition.

People with the post-COVID-19 condition suffer symptoms that persist beyond 12 weeks following acute COVID-19 infection. Fatigue, shortness of breath, and cognitive dysfunction ("brain fog") are common. Scientists, clinicians, and patients debate the pathophysiology. One pathophysiological hypothesis is that prothrombotic changes associated with acute COVID-19 persist, causing clots that lead to symptoms. This theory, arising from a research team in South Africa and supported by a paper in Nature Medicine, has been widely disseminated on social media and entered the public narrative as a cause of the post-COVID-19 condition. We describe the development of this theory, examine the findings of a Cochrane review that critically appraises the "microclot" beliefs, and critically appraise the influential study relating clotting biomarkers to cognitive deficits. We conclude the inferences for the hypothesis are not based on evidence, unlicensed use of antithrombotic medication is not justified, and apheresis should not be considered outside of a well-designed clinical trial.

Preventive Intake of a Multiple Micronutrient Supplement during Mild, Acute SARS-CoV-2 Infection to Reduce the Post-Acute COVID-19 Condition: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

Patients hospitalized with COVID-19 have low levels of vitamins and trace elements. This could lead to a post-acute COVID-19 condition (PCC) that can worsen a patient's quality of life. We aimed to study the baseline micronutrient status of patients and assess whether a multiple micronutrient supplement (MMS) taken for 2 weeks at the first sign of COVID-19 symptoms would be able to reduce the incidence of PCC. This double-blind, placebo-controlled, randomized clinical trial was conducted in adult outpatients with acute COVID-19, recruited between 2021 and 2023 in Spain. Of the 285 patients assessed for eligibility, 267 were randomized and 246 were included in the intent-to-treat population. The mean age was 46.8 years, and 68% were female. Overall, 54.6% had micronutrient deficiencies in the acute phase of COVID-19 at baseline, and 26.2% had PCC after 180 days of follow-up (D180). The most frequently recorded PCC symptoms were neurological (14.1%), with 24% patients scoring worse in the cognitive tests compared to their baseline status. The rate of PCC at D180 was similar between the placebo (25.0%) and intervention (27.7%) groups, without significant differences (p = 0.785). Age over 50 years was the most relevant risk factor for developing PCC, followed by female sex. The most important protective factor against PCC was SARS-CoV-2 vaccination. In this population of predominantly middle-aged, white women with acute COVID-19 not requiring hospital admission, MMS intake for 14 days at symptom onset did not prevent PCC nor improve their micronutrient status at D180.

Poor sleep quality may trigger cognitive deficits after recovery from COVID-19.

Objective: In the present study, we aimed to assess the cognition of post-COVID-19 condition (PCC) participants in relation to their subjective sleep quality (Pittsburgh Sleep Quality Index, PSQI) and to analyse possible moderators of this effect, such as quality of life (European Quality of Life-5 Dimensions, EQ-5D), fatigue (Chadler Fatigue Questionnaire, CFQ), cognitive reserve (Cognitive Reserve Questionnaire, CRC), and subjective cognitive complaints (Memory Failures of Everyday Questionnaire, MFE-30). Methods: We included 373 individuals with PCC and 126 healthy controls (HCs) from the NAUTILUS Project (NCT05307549 and NCT05307575) who were assessed with a comprehensive neuropsychological battery and various questionnaires. Results: We found that PCC participants with poor sleep quality had a 4.3% greater risk of immediate verbal memory deficits than those with good sleep quality, as indicated by the greater odds ratio (OR) of 1.043 and confidence interval (CI) of 1.023-1.063. Additionally, their risk of immediate verbal memory disorders was multiplied by 2.4 when their EQ-5D score was low (OR 0.33; CI 0.145-0.748), and they had a lower risk of delayed visual memory deficits with a greater CRC (OR 0.963; CI 0.929-0.999). With respect to processing speed, PCC participants with poor sleep quality had a 6.7% greater risk of deficits as the MFE increased (OR 1.059; CI 1.024-1.096), and the risk of slowed processing speed tripled with a lower EQ-5D (OR 0.021; CI 0.003-0.141). Conclusion: These results indicate that poor subjective sleep quality is a potential trigger for cognitive deficits. Therapeutic strategies to maximize sleep quality could include reducing sleep disturbances and perhaps cognitive impairment in PCC individuals.

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement.

Long COVID (LC), also referred to as Post COVID-19 Condition, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and other terms, represents a complex multisystem disease persisting after the acute phase of COVID-19. Characterized by a myriad of symptoms across different organ systems, LC presents significant diagnostic and management challenges. Central to the disorder is the role of low-grade inflammation, a non-classical inflammatory response that contributes to the chronicity and diversity of symptoms observed. This review explores the pathophysiological underpinnings of LC, emphasizing the importance of low-grade inflammation as a core component. By delineating the pathogenetic relationships and clinical manifestations of LC, this article highlights the necessity for an integrated approach that employs both personalized medicine and standardized protocols aimed at mitigating long-term consequences. The insights gained not only enhance our understanding of LC but also inform the development of therapeutic strategies that could be applicable to other chronic conditions with similar pathophysiological features.

Headache severity in patients with post COVID-19 condition: a case-control study.

Post COVID-19 conditions (PCC) present with a wide range of symptoms. Headache is one of the most frequently reported neurological symptoms by patients with PCC. We aimed to assess the prevalence of headache in patients with PCC who attended the Post-COVIDLMU outpatient department at LMU University Hospital in Munich. We hypothesized that headaches occur more frequently in patients with PCC than in the control group. Patients answered a questionnaire containing sociodemographic characteristics, their current symptoms, and prior psychiatric and somatic diagnoses, the WHO Quality of Life assessment (WHOQOL-BREF), 9-item Patient Health Questionnaire (PHQ-9), and the Fatigue Severity Scale (FSS). 188 PCC patients were included in this study and compared to a control group of patients with a history of COVID-19 or a different infectious disease - but no consecutive post-infectious condition (nc=27). 115 (61%) of our PCC patients were female. The median age was 41 years. 60 (32%, p = 0.001) had a pre-existing psychiatric diagnosis. PCC was associated with worse outcomes in all four domains of the WHOQOL-BREF (p < 0.001), high levels of fatigue (FSS; p < 0.001), and a higher likeliness for symptoms of depression (PHQ-9; p < 0.001). We were able to confirm that psychiatric disorders are more frequently associated with headaches in PCC patients. Headache should be assessed and treated in the context of PCC not only by neurologists but by multi-professional teams and regarding all PCC symptoms.

Sex-specific biphasic alpha-synuclein response and alterations of interneurons in a COVID-19 hamster model.

BACKGROUND: Coronavirus disease 2019 (COVID-19) frequently leads to neurological complications after recovery from acute infection, with higher prevalence in women. However, mechanisms by which SARS-CoV-2 disrupts brain function remain unclear and treatment strategies are lacking. We previously demonstrated neuroinflammation in the olfactory bulb of intranasally infected hamsters, followed by alpha-synuclein and tau accumulation in cortex, thus mirroring pathogenesis of neurodegenerative diseases such as Parkinson's or Alzheimer's disease. METHODS: To uncover the sex-specific spatiotemporal profiles of neuroinflammation and neuronal dysfunction following intranasal SARS-CoV-2 infection, we quantified microglia cell density, alpha-synuclein immunoreactivity and inhibitory interneurons in cortical regions, limbic system and basal ganglia at acute and late post-recovery time points. FINDINGS: Unexpectedly, microglia cell density and alpha-synuclein immunoreactivity decreased at 6 days post-infection, then rebounded to overt accumulation at 21 days post-infection. This biphasic response was most pronounced in amygdala and striatum, regions affected early in Parkinson's disease. Several brain regions showed altered densities of parvalbumin and calretinin interneurons which are involved in cognition and motor control. Of note, females appeared more affected. INTERPRETATION: Our results demonstrate that SARS-CoV-2 profoundly disrupts brain homeostasis without neuroinvasion, via neuroinflammatory and protein regulation mechanisms that persist beyond viral clearance. The regional patterns and sex differences are in line with neurological deficits observed after SARS-CoV-2 infection. FUNDING: Federal Ministry of Health, Germany (BMG; ZMV I 1-2520COR501 to G.G.), Federal Ministry of Education and Research, Germany (BMBF; 03COV06B to G.G.), Ministry of Science and Culture of Lower Saxony in Germany (14-76403-184, to G.G. and F.R.).

Association between fatigue and depressive symptoms in persons with post-COVID-19 condition: a post hoc analysis.

OBJECTIVE: Post-COVID-19 Condition (PCC) is a prevalent, persistent and debilitating phenomenon occurring three or more months after resolution of acute COVID-19 infection. Fatigue and depressive symptoms are commonly reported in PCC. We aimed to further characterize PCC by assessing the relationship between fatigue and depressive symptom severity in adults with PCC. METHODS: A post hoc analysis was conducted on data retrieved from a randomized, double-blinded, placebo-controlled study evaluating vortioxetine for cognitive deficits in persons with PCC. We sought to determine the relationship between baseline fatigue [i.e. Fatigue Severity Scale (FSS) total score] and baseline depressive symptom severity [i.e. 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR-16) total score] in adults with PCC. RESULTS: The statistical analysis included baseline data from 142 participants. After adjusting for age, sex, education, employment status, history of major depressive disorder (MDD) diagnosis, self-reported physical activity, history of documented acute SARS-CoV-2 infection and body mass index (BMI), baseline FSS was significantly correlated with baseline QIDS-SR-16 (ß = 0.825, p = .001). CONCLUSION: In our sample, baseline measures of fatigue and depressive symptoms are correlated in persons living with PCC. Individuals presenting with PCC and fatigue should be screened for the presence and severity of depressive symptoms. Guideline-concordant care should be prescribed for individuals experiencing clinically significant depressive symptoms. Fatigue and depressive symptom severity scores were not pre-specified as primary objectives of the study. Multiple confounding factors (i.e. disturbance in sleep, anthropometrics and cognitive impairment) were not collected nor adjusted for in the analysis herein. TRIAL REGISTRATION: Unrestricted Research Grant from H. Lundbeck A/S, Copenhagen, Denmark. ClinicalTrials.gov Identifier: NCT05047952.

Likelihood of Post-COVID Condition in people with hybrid immunity; data from the German National Cohort (NAKO).

OBJECTIVES: The risk of Post-COVID-19 condition (PCC) under hybrid immunity remains unclear. METHODS: Using data from the German National Cohort (NAKO Gesundheitsstudie), we investigated risk factors for self-reported post-infection symptoms (any PCC is defined as having at least one symptom, and high symptom burden PCC as having nine or more symptoms). RESULTS: Sixty percent of 109,707 participants reported at least one previous SARS-CoV-2 infection; 35% reported having had any symptoms 4-12 months after infection; among them 23% reported nine or more symptoms. Individuals, who did not develop PCC after their first infection, had a strongly reduced risk for PCC after their second infection (50%) and a temporary risk reduction, which waned over 9 months after the preceding infection. The risk of developing PCC strongly depended on the virus variant. Within variants, there was no effect of the number of preceding vaccinations, apart from a strong protection by the fourth vaccination compared to three vaccinations for the Omicron variant (odds ratio = 0.52; 95% confidence interval 0.45-0.61). CONCLUSIONS: Previous infections without PCC and a fourth vaccination were associated with a lower risk of PCC after a new infection, indicating diminished risk under hybrid immunity. The two components of risk reduction after a preceding infection suggest different immunological mechanisms.