"Actionable" host genetic markers for repurposing "add-on therapy" in COVID-19

Background/Objectives: COVID-19 still represents a lifethreatening disease in individuals with a specific genetic background. We successfully applied a new Machine Learning method on WES data to extract a set of coding variants relevant for COVID- 19 severity. We aim to identify personalized add-on therapy. Method(s): A subset of identified variants, "actionable" by repurposed drugs, were functionally tested by in vitro and in vivo experiments. Result(s): Males with either rare loss of function variants in the TLR7 gene or L412F polymorphism in the TLR3 gene benefit from IFN-gamma, which is specifically defective in activated PBMCs, restoring innate immunity. Females heterozygous for rare variants in the ADAMTS13 gene and males with D603N homozygous polymorphism in the SELP gene benefit from Caplacizumab, which reduces vWF aggregation and thrombus formation. Males with either the low-frequency gain of function variant T201M in CYP19A1 gene or with poly-Q repeats >=23 in the AR gene benefit from Letrozole, an aromatase inhibitor, which restores normal testosterone levels, reducing inflammation and which rescues male golden hamsters from severe COVID-19. Conclusion(s): By adding these commonly used drugs to standard of care of selected patients, the rate of intubation is expected to decrease consistently, especially in patients with high penetrance rare genetic markers, mitigating the effect of the pandemic with a significant impact on the healthcare system.

Substance Use Among Physician Assistant Students: A National Study on the Prevalence of Alcohol, Tobacco, Illicit Substances, and Medication Use.

INTRODUCTION: The purpose of this study was to discover the substance use prevalence among physician assistant students (PA-S) compared with the age-relevant general US population and to examine the frequency of stress, burnout, anxiety, and depression during the didactic and clinical phases, while accounting for the impact of the COVID-19 pandemic. METHODS: A 20-item survey instrument was created. Self-reported data included demographics, anxiety, burnout, tobacco, illicit substances, and prescription medication use. Outcome-based inventories included a modified Perceived Stress Scale, Patient Health Questionnaire-2 (PHQ-2), and Alcohol Use Disorder Identification Test-Concise. The survey was emailed to all US programs (∼270 programs; ∼25,000 students), with 54 programs approving dissemination to their students (n∼4,760). RESULTS: Of the 1432 responses (30% response rate, 96% completion rate), the final validated sample was 1378 students (56.1% didactic, 43.8% clinical). When compared with the national population, PA-S prevalence for tobacco (5.2%) and illicit substance use (9.9%) were notably lower; alcohol (53.5%) was comparable; and prescription medication (7.0%) is only reported for PA students due to the lack of a national comparison. A higher frequency of substance use was observed during the didactic (52.5%) vs clinical (47.5%) phases. Stress was the dominant factor in both phases (93.5% didactic, 86.1% clinical). Respondents reported that the COVID-19 pandemic had minimal impact on reported rates, other than alcohol. DISCUSSION: Although PA-S substance use prevalence is at or below the national population, PA programs are encouraged to review their policies and provide conversations and resources for students who may have one or more risk factors and experience a negative effect from current substance use.

Social and moral psychology of COVID-19 across 69 countries.

The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables.

Intensity and frequency of extreme novel epidemics.

Observational knowledge of the epidemic intensity, defined as the number of deaths divided by global population and epidemic duration, and of the rate of emergence of infectious disease outbreaks is necessary to test theory and models and to inform public health risk assessment by quantifying the probability of extreme pandemics such as COVID-19. Despite its significance, assembling and analyzing a comprehensive global historical record spanning a variety of diseases remains an unexplored task. A global dataset of historical epidemics from 1600 to present is here compiled and examined using novel statistical methods to estimate the yearly probability of occurrence of extreme epidemics. Historical observations covering four orders of magnitude of epidemic intensity follow a common probability distribution with a slowly decaying power-law tail (generalized Pareto distribution, asymptotic exponent = -0.71). The yearly number of epidemics varies ninefold and shows systematic trends. Yearly occurrence probabilities of extreme epidemics, Py, vary widely: Py of an event with the intensity of the "Spanish influenza" (1918 to 1920) varies between 0.27 and 1.9% from 1600 to present, while its mean recurrence time today is 400 y (95% CI: 332 to 489 y). The slow decay of probability with epidemic intensity implies that extreme epidemics are relatively likely, a property previously undetected due to short observational records and stationary analysis methods. Using recent estimates of the rate of increase in disease emergence from zoonotic reservoirs associated with environmental change, we estimate that the yearly probability of occurrence of extreme epidemics can increase up to threefold in the coming decades.

SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice.

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.

Anxiety is more related to inadequate eating habits in inactive than in physically active adults during COVID-19 quarantine.

BACKGROUND & AIMS: Anxiety can be related to reduced diet quality during pandemics such as COVID-19. However, it is not clear whether these relationships would be similar in inactive and physically active participants. The aim of this study was to analyze associations between anxiety and eating habits in physically active and inactive individuals during the COVID-19 pandemic. METHODS: The sample consisted of 1826 adults (58.5% women) who were invited through social media to answer an online questionnaire. The instrument included questions related to physical activity, eating habits, health behavior, mental health (anxiety, depression, self-esteem, sadness and stress) and overall health. Anxiety, food habits (high food habits consumption ≥5 times per week) and physical activity (≥150 min per week) were assessed during the COVID-19 pandemic. The relationship between anxiety and eating habits according to levels of physical activity (inactive vs. active) was assessed using binary logistic regression adjusted for sex, age, education level, social isolation, and body mass index. RESULTS: Among the inactive participants, anxiety was related with high consumption of sweets (OR = 1.43; 95% CI = 1.11-1.83) and fast foods (OR = 2.23; 95% CI = 1.05-4.74) while quarantining during the COVID-19 pandemic. No relationship was observed between anxiety and food consumption among physically active participants in the final model. CONCLUSION: Anxiety was associated with less desirable eating habits among physically inactive adults during the COVID-19 pandemic.

Learning Anatomy in a developing country under COVID‐19 lockdown measures: How did the learners perceive it?

Introduction Acknowledging the fundamental role anatomy education plays in medical training and taking into consideration the nascence of online anatomy education in Nigeria, we evaluated the current and future perceptions of medical and allied‐health students towards online anatomy education during the COVID‐19 lockdown in Nigeria. Methods Google Form questionnaires were distributed via different social and academic platforms to medical and allied‐health students in Nigeria between September 28 –December 17, 2020, using a purposive sampling. 954 students responded to questions on what they felt about the online anatomy teaching including how it could affect their academic performance in anatomy. Additionally, they were asked to give their opinion of the future of e‐learning in anatomy in Nigeria. The data collected from the study were analyzed using descriptive and inferential techniques. Results Out of a total of 954 students who participated in the study, 947 valid responses were recorded. From the responses, most of the students (77.6%) had computer/IT skills. Unexpectedly, many of the students (60%) did not favor online learning approaches as effective tools for instructions in the anatomical sciences while more than a half of the students (55%) did not find the online classes in anatomy interesting. On the other hand, a majority (84%) believed that physical classes would have improved their performance in anatomy. Almost all the students (91.5%) believed anatomy educators in Nigeria need advanced skills for online education and that anatomy online teaching needs more advanced technology to be implemented in Nigeria(94.2%). Conclusion After evaluating online anatomy education experience during the COVID‐19 lockdown in Nigeria from medical and allied‐health students’ position, it was observed that there was an inclusive negative perception about the suitability and effectiveness of online education with regards to the anatomical sciences in Nigerian medical/health training. Majority of the students indicated that there is need for the enhancement of online teaching and quality training of the anatomy educators. Addressing the challenges that were presented during online anatomy education at the heat of the pandemic is recommended. This will incline science education towards the development and implementation of a workable and sustainable online education model in anatomical sciences for Nigeria.

Efficacy and effectiveness of ultraviolet radiation as a procedure to carry out the hospital environmental decontamination

introduction. The hospital surfaces can contribute to secondary cross contamination, through the hands of health care personnel or contaminated material. It has been necessary to develop ambiental automatic decontamination equipment without the problems related with manual disinfection. material and method. An analytical, prospective, cross-sectional study was carried out, to evaluate the the efficacy and effectiveness of ambiental decontamination at the hospital, with ultraviolet radiation of a 245 nm wavelength equipment, on two semi critical areas, meant for clinical attention to patients with sars-cov-2 infection, with pre and post intervention sampling. 2-stage study to evaluate efficiency and effectiveness. results. In stage 1 (efficacy evaluation) atcc reference strains were sown, subsequently intervention with uv radiation was carried out, the growth of microorganisms was 0/3 in the micas, that is;it was possible to eliminate the bacterial load in 100% (3 samples). In stage 2 (evaluation of effectiveness), microbiological samples were taken from 15 clinic sites under baseline conditions, it was found that there was growth of microorganisms on 12/15 surfaces prior to intervention. After decontamination with uv radiation, the growth of microorganisms was 4/15 in the micas, bacterial elimination was achieved in 73.34% of the sampled surfaces and the bacterial load persisted in 26.66% of the sampled areas. After the decontamination intervention through uv light, a significant bacterial count elimination was achieved (Chi Square test p = 0.0002). conclusions. The decontamination process with uv light in closed spaces with equipment that emits radiation with a wavelength of 254 nm for 30 minutes was an effective intervention to reduce and eliminate the bacterial load from hospital surfaces.

Impact of COVID-19 pandemic on physical activity level and screen time is associated with decreased mental health in Brazillian adults: A cross-sectional epidemiological study.

The objective was to verify whether the impact of COVID-19 on physical activity and screen time was associated with the impact on quality of life and symptoms of anxiety and depression in a sample of Brazilian adults. The invitation was made through social networks and the collection was carried out through electronic research. There was a decrease in quality of life and physical activity, and an increase in symptoms of anxiety and depression and screen time. These findings are important for new strategies that promote physically active habits during the pandemic .

SARS-CoV-2 spike protein induces long-term TLR4-mediated synapse and cognitive loss recapitulating Post-COVID syndrome (preprint)

COVID-19 pandemic affected the global population in an unprecedented scale, with long-term consequences of SARS CoV-2 infection now emerging as a serious concern. Cognitive dysfunction is often reported in post-COVID patients, but its underlying mechanisms remain unknown. Here we demonstrated that brain exposure to SARS-CoV-2 spike (S) protein through its infusion into the lateral ventricle of adult mice induced late cognitive impairment, hippocampal synapse loss, and microglial engulfment of presynaptic terminals. Additionally, TLR4 blockage prevented Sassociated detrimental effects on memory in mice and TLR4 single nucleotide polymorphism (SNP) rs10759931 was associated with late cognitive outcome in mild COVID-19-recovered patients. Collectively, these findings indicate that S protein directly impacts the brain and identify TLR4 as a key target to prevent cognitive dysfunction. To our knowledge, this is the first animal model that recapitulates postCOVID cognitive impairment, opening new avenues for developing new strategies to prevent or treat the neurological outcomes of COVID-19.

Depressive Symptoms Associated With Musculoskeletal Pain in Inactive Adults During COVID-19 Quarantine

Background Depression has been associated with episodes of musculoskeletal pain. However, it is not clear whether such relationships could be mitigated according to the physical activity level. Aim To describe, during the COVID-19 pandemic, the relationship between depression and musculoskeletal pain according to the physical activity levels. Design Cross-sectional study. Methods This research was conducted in Brazil between May 5 and March 17, 2020. Participants (N = 1872;58% women) were invited through social media to answer a structured online questionnaire. Depressive symptoms were assessed through self-report of perception of depression during quarantine. Musculoskeletal pain was assessed based on the Nordic questionnaire identifying nine possible pain points in the body. Physical activity was assessed based on the weekly frequency, intensity, and duration of each session of physical activity the participants engaged in during COVID-19. The logistic binary regression analyzed the associations between depressive symptoms and musculoskeletal pain according to the participants’ level of physical activity. Results Depressive symptoms were associated with pain in six different regions of the body in physically inactive participants. In physically inactive participants, those with depressive symptoms 1.51 (95% CI = 1.04-2.19) and 2.78 (95% CI = 1.81-4.26) times more likely to have pain in one or two and ≥three regions body regions, respectively. In active participants, depressive symptoms were not associated with pain. Conclusion During the COVID-19 pandemic, depression was associated with musculoskeletal pain in physically inactive participants.

Zebrafish as a Translational Model: An Experimental Alternative to Study the Mechanisms Involved in Anosmia and Possible Neurodegenerative Aspects of COVID-19?

The Coronavirus disease-2019 (COVID-19) presents a variability of clinical symptoms, ranging from asymptomatic to severe respiratory and systemic conditions. In a cohort of patients, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), beyond the classical respiratory manifestations, induces anosmia. Evidence has suggested SARS-CoV-2-induced anosmia can be the result of neurodegeneration of the olfactory pathway. Neurologic symptoms associated with COVID-19 have been reported; however, the precise mechanism and possible long-lasting effects remain poorly investigated. Preclinical models are valuable tools for describing and testing new possible treatments for neurologic disorders. In this way, the zebrafish (Danio rerio) organism model represents an attractive tool in the field of neuroscience, showing economic and logistic advantages besides genetic and physiologic similarities with mammalian, including the brain structure and functions. Besides, its external embryonic development, high availability of eggs, and fast development allows easy genetic manipulation and fast replications. In the present review, we suggest that the zebrafish model can be advantageous to investigate the neurologic features of COVID-19.

A kernel-modulated SIR model for Covid-19 contagious spread from county to continent.

The tempo-spatial patterns of Covid-19 infections are a result of nested personal, societal, and political decisions that involve complicated epidemiological dynamics across overlapping spatial scales. High infection "hotspots" interspersed within regions where infections remained sporadic were ubiquitous early in the outbreak, but the spatial signature of the infection evolved to affect most regions equally, albeit with distinct temporal patterns. The sparseness of Covid-19 infections in the United States was analyzed at scales spanning from 10 to 2,600 km (county to continental scale). Spatial evolution of Covid-19 cases in the United States followed multifractal scaling. A rapid increase in the spatial correlation was identified early in the outbreak (March to April). Then, the increase continued at a slower rate and approached the spatial correlation of human population. Instead of adopting agent-based models that require tracking of individuals, a kernel-modulated approach is developed to characterize the dynamic spreading of disease in a multifractal distributed susceptible population. Multiphase Covid-19 epidemics were reasonably reproduced by the proposed kernel-modulated susceptible-infectious-recovered (SIR) model. The work explained the fact that while the reproduction number was reduced due to nonpharmaceutical interventions (e.g., masks, social distancing, etc.), subsequent multiple epidemic waves still occurred; this was due to an increase in susceptible population flow following a relaxation of travel restrictions and corollary stay-at-home orders. This study provides an original interpretation of Covid-19 spread together with a pragmatic approach that can be imminently used to capture the spatial intermittency at all epidemiologically relevant scales while preserving the "disordered" spatial pattern of infectious cases.

Vascular Inflammation Is Associated with Loss of Aquaporin 1 Expression on Endothelial Cells and Increased Fluid Leakage in SARS-CoV-2 Infected Golden Syrian Hamsters

Vascular changes represent a characteristic feature of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leading to a breakdown of the vascular barrier and subsequent edema formation. The aim of this study was to provide a detailed characterization of the vascular alterations during SARS-CoV-2 infection and to evaluate the impaired vascular integrity. Groups of ten golden Syrian hamsters were infected intranasally with SARS-CoV-2 or phosphate-buffered saline (mock infection). Necropsies were performed at 1, 3, 6, and 14 days post-infection (dpi). Lung samples were investigated using hematoxylin and eosin, alcian blue, immunohistochemistry targeting aquaporin 1, CD3, CD204, CD31, laminin, myeloperoxidase, SARS-CoV-2 nucleoprotein, and transmission electron microscopy. SARS-CoV-2 infected animals showed endothelial hypertrophy, endothelialitis, and vasculitis. Inflammation mainly consisted of macrophages and lower numbers of T-lymphocytes and neutrophils/heterophils infiltrating the vascular walls as well as the perivascular region at 3 and 6 dpi. Affected vessels showed edema formation in association with loss of aquaporin 1 on endothelial cells. In addition, an ultrastructural investigation revealed disruption of the endothelium. Summarized, the presented findings indicate that loss of aquaporin 1 entails the loss of intercellular junctions resulting in paracellular leakage of edema as a key pathogenic mechanism in SARS-CoV-2 triggered pulmonary lesions.

Physical Activity Is Associated With Improved Eating Habits During the COVID-19 Pandemic.

The aim of this study was to analyze the association between physical activity and eating habits during the COVID-19 pandemic among Brazilian adults. A sample of 1,929 participants answered an online survey, however 1,874 were included in the analysis. The impact of the COVID-19 pandemic on eating habits was assessed inquiring about participants' intake of fruits, vegetables, fried foods, and sweets during the pandemic. Physical activity was assessed by asking participants about their weekly frequency, intensity and number of minutes/hours engaging in structured physical activities per week. Participants were then stratified into categories based on moderate-to-vigorous intensity (0-30; 31-90; 91-150; 151-300; and >300 min/week) and into active (≥150 min) or inactive (<150 min). Increased sweets consumption was the most commonly reported change to eating habits (42.5%), followed by an increase in the consumption of vegetables (26.6%), fruits (25.9%), and fried foods (17.9%). Physical activity practice was related to lower consumption of fried foods (OR = 0.60; p < 0.001) and sweets (OR = 0.53; p < 0.001). A cluster analysis revealed subjects with higher the level of physical activity was more likely to follow a healthy diet (p < 0.001). Thus, physical activity was positively associated with healthier eating habits. Health authorities must recommend regular physical as a strategy to improve overall health during the COVID-19 pandemic. Future studies should address the physical activity interventions to improve health status during a pandemic.

Increased Screen Time Is Associated With Alcohol Desire and Sweetened Foods Consumption During the COVID-19 Pandemic.

Background: Elevated screen time has been associated with addictive behaviors, such as alcohol and sugar intake and smoking. Considering the substantial increase in screen time caused by social isolation policies, this study aimed to analyze the association of increased screen time in different devices during the COVID-19 pandemic with consumption and increased desire of alcohol, smoking, and sweetened foods in adults. Methods: A sample of 1,897 adults with a mean age of 37.9 (13.3) years was assessed by an online survey, being composed by 58% of women. Participants were asked whether screen time in television, cell phone, and computer increased during the pandemic, as well as how much time is spent in each device. Closed questions assessed the frequency of alcohol and sweetened food consumption, smoking, and an increased desire to drink and smoke during the pandemic. Educational level, age, sex, feeling of stress, anxiety, depression, and use of a screen device for physical activity were covariates. Binary logistic regression models considered adjustment for covariates and for mutual habits. Results: Increased television time was associated with increased desire to drink (OR = 1.46, 95% CI: 1.12; 1.89) and increased sweetened food consumption (OR = 1.53, 95% CI: 1.18; 1.99), while an increase in computer use was negatively associated with consumption of alcohol (OR = 0.68, 95% CI: 0.53; 0.86) and sweetened foods (OR = 0.78, 95% CI: 0.62; 0.98). Increased cell phone time was associated with increased sweetened food consumption during the pandemic (OR = 1.78, 95% CI: 1.18; 2.67). Participants with increased time in the three devices were less likely to consume sweetened foods for ≥5 days per week (OR = 0.63, 95% CI: 0.39; 0.99) but were twice as likely to have sweetened food consumption increased during pandemic (OR = 2.04, 95% CI: 1.07; 3.88). Conclusion: Increased screen time was differently associated with consumption and desire for alcohol and sweets according to screen devices. Increased time in television and cell phones need to be considered for further investigations of behavioral impairments caused by the pandemic.

Reduction of Physical Activity Levels During the COVID-19 Pandemic Might Negatively Disturb Sleep Pattern.

BACKGROUND: The outbreak of novel coronavirus disease 2019 (COVID-19) has caused a global panic and public concern due to its mortality ratio and lack of treatments/vaccines. Reduced levels of physical activity have been reported during the outbreak, affecting the normal daily pattern. OBJECTIVE: To investigate (i) the relationship of physical activity level with sleep quality and (ii) the effects of reduction physical activity levels on sleep quality. METHODS: A Google form was used to address personal information, COVID-19 personal care, physical activity, and mental health of 1,907 adult volunteers. Binary logistic regression was used to verify the association of physical activity parameters and sleep quality. RESULTS: Insufficient physical activity levels were a risk factor to have disturbed sleep pattern [OR: 1.28, 95% CI (1.01-1.62)]; however, when the BMI was added to the analysis, there was no more statistical difference [OR: 1.23, 95% CI (0.96-1.57)]. On the other hand, we found that the reduction of physical activity levels was associated with negative changes in sleep quality [OR: 1.73, 95% CI (1.37-2.18)], regardless all the confounders [OR: 1.30, 95% CI (1.01-1.68)], unless when feeling of depression was added in Model 6 [OR: 1.28, 95% CI (0.99-1.66)]. CONCLUSION: Disruption in daily physical activity routine, rather than physical activity level, negatively influences sleep quality during the COVID-19 quarantine.