A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. Few systematic studies have investigated this population, particularly in outpatient settings. Hence, relatively little is known about symptom makeup and severity, expected clinical course, impact on daily functioning, and return to baseline health. We conducted an online survey of people with suspected and confirmed COVID-19, distributed via COVID-19 support groups (e.g. Body Politic, Long COVID Support Group, Long Haul COVID Fighters) and social media (e.g. Twitter, Facebook). Data were collected from September 6, 2020 to November 25, 2020. We analyzed responses from 3762 participants with confirmed (diagnostic/antibody positive; 1020) or suspected (diagnostic/antibody negative or untested; 2742) COVID-19, from 56 countries, with illness lasting over 28 days and onset prior to June 2020. We estimated the prevalence of 203 symptoms in 10 organ systems and traced 66 symptoms over seven months. We measured the impact on life, work, and return to baseline health. For the majority of respondents (>91%), the time to recovery exceeded 35 weeks. During their illness, participants experienced an average of 55.9+/- 25.5 (mean+/-STD) symptoms, across an average of 9.1 organ systems. The most frequent symptoms after month 6 were fatigue, post-exertional malaise, and cognitive dysfunction. Symptoms varied in their prevalence over time, and we identified three symptom clusters, each with a characteristic temporal profile. 85.9% of participants (95% CI, 84.8% to 87.0%) experienced relapses, primarily triggered by exercise, physical or mental activity, and stress. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 1700 respondents (45.2%) required a reduced work schedule compared to pre-illness, and an additional 839 (22.3%) were not working at the time of survey due to illness. Cognitive dysfunction or memory issues were common across all age groups (~88%). Except for loss of smell and taste, the prevalence and trajectory of all symptoms were similar between groups with confirmed and suspected COVID-19. Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden. All authors contributed to this work in a voluntary capacity. The cost of survey hosting (on Qualtrics) and publication fee was covered by AA's research grant (Wellcome Trust/Gatsby Charity via Sainsbury Wellcome center, UCL).

Significance: Many higher cognitive functions involve working memory (WM), the storage and manipulation of information across limited time intervals. Comparing the WM capacity of different species is a key step toward understanding the underlying brain mechanisms. This study uncovers previously unknown sensory WM abilities in rats. They received two vibratory stimuli on their whiskers, separated by a variable delay, and had to compare vibration features. In analogous experiments, human subjects compared two stimuli applied to the fingertip. The acuity shown by rats in judging stimulus differences and their WM proficiency (across delays of 8 s, the longest tested) overlapped those of humans. Sensory WM now joins other cognitive functions within the rodent repertoire, setting the stage for exploration of its neuronal coding.

Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds, and in rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and in ex vivo human brain slices, although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial-specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. We apply this approach to Hevin knockout mice, where AAV-X1-mediated ectopic expression of the synaptogenic protein Sparcl1/Hevin in brain endothelial cells rescued synaptic deficits.

Growing evidence shows that a significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. Few systematic studies exist which investigate this population, and hence, relatively little is known about the range in symptom makeup and severity, expected clinical course, impact on daily functioning, and expected return to baseline health. In this study, we analysed responses from 3,762 participants with confirmed (diagnostic/antibody positive; 1,020) or suspected (diagnostic/antibody negative or untested; 2,742) COVID-19, from 56 countries, with illness duration of at least 28 days. 3608 (96%) reported symptoms beyond 90 days. Prevalence of 205 symptoms in 10 organ systems was estimated in this cohort, with 66 symptoms traced over seven months. Except for loss of smell and taste, the prevalence and trajectory of all symptoms were similar between groups with confirmed and suspected COVID-19. Respondents experienced an average of 14.5 symptoms in an average of 9.08 organ systems. Three clusters of symptoms were identified based on their prevalence over time. The most likely early symptoms were fatigue, dry cough, shortness of breath, headaches, muscle aches, chest tightness, and sore throat. The most frequent symptoms reported after month 6 were fatigue, post-exertional malaise, and cognitive dysfunction. Majority (>85%) experienced relapses, with exercise, physical or mental activity, and stress as the main triggers. 1,700 (45.2%) reported requiring a reduced work schedule compared to pre-illness and 839 (22.3%) were not working at the time of survey due to their health conditions. Significance Statement: Results from our international online survey of 3,762 individuals with suspected or confirmed COVID-19 illness suggest that Long COVID is composed of heterogeneous post-acute infection sequelae that often affect multiple organ systems, with impact on functioning and quality of life ranging from mild to severe. This study represents the largest collection of symptoms identified in the Long COVID population to date, and is the first to quantify individual symptom trajectory over time, for 7 months. Three clusters of symptoms were quantified, each with different morphologies over time. The clusters of symptoms that persist longest include a combination of the neurological/cognitive and systemic symptoms. The reduced work capacity because of cognitive dysfunction, in addition to other debilitating symptoms, translated into the loss of hours, jobs, and ability to work relative to pre-illness levels. Structured Objective: To characterize the symptom profile and time course in patients with Long COVID, along with the impact on daily life, work, and return to baseline health. Design: International web-based survey of suspected and confirmed COVID-19 cases with illness lasting over 28 days and onset prior to June 2020. Setting: Survey distribution via online COVID-19 support groups and social media Participants: 3,762 respondents from 56 countries completed the survey. 1166 (31.0%) were 40-49 years old, 937 (25.0%) were 50-59 years old, 905 (24.1%) were 30-39 years old, 277 (7.4%) were 18-29 years old, and 477 (12.7%) were above 60 years old. 2961 (78.9%) were women, 718 (19.1%) were men, and 63 (1.7%) were nonbinary. 317 (8.4%) reported being hospitalized. 1020 (27.1%) reported receiving a laboratory-confirmed diagnosis of COVID-19. 3608 (96%) reported symptoms beyond 90 days. Results: Prevalence of 205 symptoms in 10 organ systems was estimated in this cohort, with 66 symptoms traced over seven months. Except for loss of smell and taste, the prevalence and trajectory of all other symptoms are similar between confirmed (diagnostic/antibody positive) and suspected groups (diagnostic/antibody negative or untested). Respondents experienced symptoms in an average of 9.08 (95% confidence interval 9.04 to 9.13) organ systems. The most frequent symptoms reported after month 6 were: fatigue (77.7%, 74.9% to 80.3%), post-exertional malaise (72.2%, 69.3% to 75.0%), and cognitive dysfunction (55.4%, 52.4% to 58.8%). These three symptoms were also the three most commonly reported overall. In those who recovered in less than 90 days, the average number of symptoms peaked at week 2 (11.4, 9.4 to 13.6), and in those who did not recover in 90 days, the average number of symptoms peaked at month 2 (17.2, 16.5 to 17.8). Respondents with symptoms over 6 months experienced an average of 13.8 (12.7 to 14.9) symptoms in month 7. 85.9% (84.8% to 87.0%) experienced relapses, with exercise, physical or mental activity, and stress as the main triggers. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 45.2% (42.9% to 47.2%) reported requiring a reduced work schedule compared to pre-illness and 22.3% (20.5% to 24.3%) were not working at the time of survey due to their health conditions. Conclusions: Patients with Long COVID report prolonged multisystem involvement and significant disability. Most had not returned to previous levels of work by 6 months. Many patients are not recovered by 7 months, and continue to experience significant symptom burden.