Growth and characteristics of US first episode psychosis programs

Aims: In 2008, only two US states supported first-episode psychosis (FEP) programs. Today every state in the United States has a plan for supporting FEP programs, and over 350 programs currently operate across the country. In this presentation, we will describe the milestones and factors that have marked the growth of U.S. early psychosis programs and their characteristics. Method(s): Data were drawn from two national surveys fielded in 2018 and 2022. The 2018 survey data included responses from leadership at 215 early psychosis programs across the United States, and the 2022 survey data includes responses from U.S. state mental health authorities. The surveys provide information about a variety of key programmatic features of FEP clinics across the United States, including, program size, client capacity, duration of care, referral sources, services offered, funding, and outcomes measurement. Results and Discussion: Nearly 70% of the programs tie their start date to after the 2014 influx of federal funding. Services offered by the FEP programs have many similarities despite programs prescribing to specific FEP models (e.g., NAVIGATE, EASA, OnTrackNY, etc.). The surveys show program-level changes that have occurred between 2018 and 2022 and offer historical and data-driven explanations for how FEP programs have developed. The 2022 survey data also provide information regarding how States have chosen to implement the additional COVID-19 emergency funds designated for early psychosis programming.

Return to elite football after the COVID-19 lockdown

The COVID-19 pandemic has changed the conditions for competitive football around the globe dramatically. Several competitions and leagues have been cancelled or postponed. Players have firstly been forced to training in solitude. In a second stage, players start training in small groups with strict contact restriction and return to competitive play might occur after only few weeks of normal team training preparation. These special circumstances are likely to impact football performance and injury risk in the upcoming competitions. Thus, clubs, coaching and medical staff, as well as players are challenged on the prioritization of fitness and performance, which easily can create several "catch-22-dilemmas”. The present article presents views on fitness training, physical preparation and recovery during these uncommon conditions, and how elite football players can return to the competitive field well-prepared for post-crisis football endeavours around the world. Due to the multifaceted physiological demands in elite football, the long recovery requirements after match-play and an upcoming reality with many games within a short period, elite football players, managers and clubs may face extraordinary challenges associated with return to play under the current circumstances.

Safety of COVID-19 vaccines in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Data are sparse regarding the safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (MS). OBJECTIVE: To estimate (1) the pooled proportion of MS patients experiencing relapse among vaccine recipients; (2) the rate of transient neurological worsening, adverse events, and serious adverse events; (3) the previous outcomes of interest for different SARS-CoV-2 vaccine types. METHODS: Systematic review and meta-analysis of pharmacovigilance registries and observational studies. RESULTS: Nineteen observational studies comprising 14,755 MS patients who received 23,088 doses of COVID-19 vaccines were included. Mean age was 43.3 years (95% confidence interval (CI): 40-46.6); relapsing-remitting, secondary-progressive, primary-progressive MS and clinically isolated syndrome were diagnosed in 82.6% (95% CI: 73.9-89.8), 12.6% (95% CI: 6.3-20.8), 6.7% (95% CI: 4.2-9.9), and 2.9% (95% CI: 1-5.9) of cases, respectively. The pooled proportion of MS patients experiencing relapse at a mean time interval of 20 days (95% CI: 12-28.2) from vaccination was 1.9% (95% CI: 1.3%-2.6%; I2 = 78%), with the relapse risk being independent of the type of administered SARS-CoV-2-vaccine (p for subgroup differences = 0.7 for messenger RNA (mRNA), inactivated virus, and adenovector-based vaccines). After vaccination, transient neurological worsening was observed in 4.8% (95% CI: 2.3%-8.1%) of patients. Adverse events and serious adverse events were reported in 52.8% (95% CI: 46.7%-58.8%) and 0.1% (95% CI: 0%-0.2%) of vaccinations, respectively. CONCLUSION: COVID-19 vaccination does not appear to increase the risk of relapse and serious adverse events in MS. Weighted against the risks of SARS-CoV-2-related complications and MS exacerbations, these safety data provide compelling pro-vaccination arguments for MS patients.

Comparing media coverage of the pharmaceutical industry: pre- and post-pandemic lockdown

PurposeThe purpose of this paper is to analyze media coverage of the pharmaceutical industry before and after the COVID-19 lockdown to determine whether the coverage changed in light of a global health-care crisis and the fast-track development of vaccines and antiviral treatments.Design/methodology/approachThe top five US newspapers were audited, comparing the 12-month periods before and after March 2020 coinciding with the pandemic lockdown, yielding 493 front-page articles and editorials. Each headline and full-text article was separately analyzed and categorized as either positive, negative or neutral toward the pharmaceutical industry. A frequency analysis of the hot button issues covered in each article was conducted.FindingsYear 1 and Year 2 audit results were compared to identify changes in media coverage pre- and post-lockdown. The amount of coverage of the industry increased 145% and the tone of both headlines and articles shifted dramatically. Only one of the five newspapers had a net positive article rating of the industry pre-lockdown, four of five were net positive post-lockdown. The proportion of positive headlines increased 165%. The top issues discussed in the coverage shifted from persistent challenges for the industry (e.g. opioid crisis, high cost of drugs) to the emergence of the virus and status of vaccine development.Originality/valueThis research establishes how media coverage of the pharmaceutical industry changed as the industry responded to a global health-care crisis and identifies implications for industry stakeholders.

HGCA2.0: An RNA-Seq Based Webtool for Gene Coexpression Analysis in Homo sapiens.

Genes with similar expression patterns in a set of diverse samples may be considered coexpressed. Human Gene Coexpression Analysis 2.0 (HGCA2.0) is a webtool which studies the global coexpression landscape of human genes. The website is based on the hierarchical clustering of 55,431 Homo sapiens genes based on a large-scale coexpression analysis of 3500 GTEx bulk RNA-Seq samples of healthy individuals, which were selected as the best representative samples of each tissue type. HGCA2.0 presents subclades of coexpressed genes to a gene of interest, and performs various built-in gene term enrichment analyses on the coexpressed genes, including gene ontologies, biological pathways, protein families, and diseases, while also being unique in revealing enriched transcription factors driving coexpression. HGCA2.0 has been successful in identifying not only genes with ubiquitous expression patterns, but also tissue-specific genes. Benchmarking showed that HGCA2.0 belongs to the top performing coexpression webtools, as shown by STRING analysis. HGCA2.0 creates working hypotheses for the discovery of gene partners or common biological processes that can be experimentally validated. It offers a simple and intuitive website design and user interface, as well as an API endpoint.

Can Water-Only DNA Extraction Reduce the Logistical Footprint of Biosurveillance and Planetary Health Diagnostics? Toward a New Method.

The coronavirus disease-2019 (COVID-19) pandemic has raised the stakes for planetary health diagnostics. Because pandemics pose enormous burdens on biosurveillance and diagnostics, reduction of the logistical burdens of pandemics and ecological crises is essential. Moreover, the disruptive effects of catastrophic bioevents impact the supply chains in both highly populated urban centers and rural communities. One "upstream" focus of methodological innovation in biosurveillance is the footprint of Nucleic Acid Amplification Test (NAAT)-based assays. We report in this study a water-only DNA extraction, as an initial step in developing future protocols that may require few expendables, and with low environmental footprints, in terms of wet and solid laboratory waste. In the present work, boiling-hot distilled water was used as the main cell lysis agent for direct polymerase chain reactions (PCRs) on crude extracts. After evaluation (1) in blood and mouth swabs for human biomarker genotyping, and (2) in mouth swabs and plant tissue for generic bacterial or fungal detection, and using different combinations of extraction volume, mechanical assistance, and extract dilution, we found the method to be applicable in low-complexity samples, but not in high-complexity ones such as blood and plant tissue. In conclusion, this study examined the doability of a lean approach for template extraction in the case of NAAT-based diagnostics. Testing our approach with different biosamples, PCR settings, and instruments, including portable ones for COVID-19 or dispersed applications, warrant further research. Minimal resources analysis is a concept and practice, vital and timely for biosurveillance, integrative biology, and planetary health in the 21st century.

Visible-Light-Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload.

Invasive fungal infections are a growing public health threat. As fungi become increasingly resistant to existing drugs, new antifungals are urgently needed. Here, it is reported that 405-nm-visible-light-activated synthetic molecular machines (MMs) eliminate planktonic and biofilm fungal populations more effectively than conventional antifungals without resistance development. Mechanism-of-action studies show that MMs bind to fungal mitochondrial phospholipids. Upon visible light activation, rapid unidirectional drilling of MMs at ≈3 million cycles per second (MHz) results in mitochondrial dysfunction, calcium overload, and ultimately necrosis. Besides their direct antifungal effect, MMs synergize with conventional antifungals by impairing the activity of energy-dependent efflux pumps. Finally, MMs potentiate standard antifungals both in vivo and in an ex vivo porcine model of onychomycosis, reducing the fungal burden associated with infection.

Impact of Stress on Health in Childhood and Adolescence.

«We must avoid with our utmost endeavour and amputate with fire and sword and by all other means: from the body, sickness; from the soul, ignorance; from the belly, luxury; from the city, sedition; from the family, discord; and from all things, excess¼ (Pythagoras of Samos, circa 569 -475 BC).

Reinfection with SARS-CoV-2 and Waning Humoral Immunity: A Case Report.

Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a different strain harboring the spike variant D614G. This case of reinfection was one of the first cases of reinfection reported in 2020. With antibody, B cell and T cell analytics, we show correlates of adaptive immunity at reinfection, including a differential response in neutralizing antibodies to a D614G pseudovirus. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.

Impact of the COVID-19 pandemic on children living in shelters and children in the community (Review)

In the first 2 years of the pandemic, from late 2019 to late 2021, several studies were conducted to determine the experience of children during the continuous lockdowns, school closures and isolation from their friends, teachers or relatives. The studies conducted included children being raised in childcare facilities and children being raised in their own homes, in various parts of the world. Numerous children worldwide, in addition to the stress and difficulties experienced by adults and minors during these years of the coronavirus disease 2019 (COVID-2019) pandemic, have experienced physical, psychological and sexual abuse. The available data indicate that the number of children presenting to hospitals with injuries from abuse has increased, despite the fact that there was a decrease in the number of reports of child abuse during the lockdowns. The financial difficulties that a number of families have faced, and continue to face, comprise the most prominent risk factor for child neglect. Additionally, a marked decrease has also been noted in the provision of care to children in care homes as regards quality. This has been mainly due to a reduction in the number of employees, either as they themselves or someone they cared for became infected with COVID-19, or as the employees and care givers suffered from exhaustion brought on by the very difficult working conditions and very strict measures taken during this period of the pandemic. [ FROM AUTHOR]

Valproate-coenzyme A conjugate blocks opening of receptor binding domains in the spike trimer of SARS-CoV-2 through an allosteric mechanism.

The receptor-binding domains (RBDs) of the SARS-CoV-2 spike trimer exhibit "up" and "down" conformations often targeted by neutralizing antibodies. Only in the "up" configuration can RBDs bind to the ACE2 receptor of the host cell and initiate the process of viral multiplication. Here, we identify a lead compound (3-oxo-valproate-coenzyme A conjugate or Val-CoA) that stabilizes the spike trimer with RBDs in the down conformation. Val-CoA interacts with three R408 residues, one from each RBD, which significantly reduces the inter-subunit R408-R408 distance by ∼ 13 Å and closes the central pore formed by the three RBDs. Experimental evidence is presented that R408 is part of a triggering mechanism that controls the prefusion to postfusion state transition of the spike trimer. By stabilizing the RBDs in the down configuration, this and other related compounds can likely attenuate viral transmission. The reported findings for binding of Val-CoA to the spike trimer suggest a new approach for the design of allosteric antiviral drugs that do not have to compete for specific virus-receptor interactions but instead hinder the conformational motion of viral membrane proteins essential for interaction with the host cell. Here, we introduce an approach to target the spike protein by identifying lead compounds that stabilize the RBDs in the trimeric "down" configuration. When these compounds trimerize monomeric RBD immunogens as co-immunogens, they could also induce new types of non-ACE2 blocking antibodies that prevent local cell-to-cell transmission of the virus, providing a novel approach for inhibition of SARS-CoV-2.

Identification and mechanistic basis of non-ACE2 blocking neutralizing antibodies from COVID-19 patients with deep RNA sequencing and molecular dynamics simulations.

Variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continue to cause disease and impair the effectiveness of treatments. The therapeutic potential of convergent neutralizing antibodies (NAbs) from fully recovered patients has been explored in several early stages of novel drugs. Here, we identified initially elicited NAbs (Ig Heavy, Ig lambda, Ig kappa) in response to COVID-19 infection in patients admitted to the intensive care unit at a single center with deep RNA sequencing (>100 million reads) of peripheral blood as a diagnostic tool for predicting the severity of the disease and as a means to pinpoint specific compensatory NAb treatments. Clinical data were prospectively collected at multiple time points during ICU admission, and amino acid sequences for the NAb CDR3 segments were identified. Patients who survived severe COVID-19 had significantly more of a Class 3 antibody (C135) to SARS-CoV-2 compared to non-survivors (15059.4 vs. 1412.7, p = 0.016). In addition to highlighting the utility of RNA sequencing in revealing unique NAb profiles in COVID-19 patients with different outcomes, we provided a physical basis for our findings via atomistic modeling combined with molecular dynamics simulations. We established the interactions of the Class 3 NAb C135 with the SARS-CoV-2 spike protein, proposing a mechanistic basis for inhibition via multiple conformations that can effectively prevent ACE2 from binding to the spike protein, despite C135 not directly blocking the ACE2 binding motif. Overall, we demonstrate that deep RNA sequencing combined with structural modeling offers the new potential to identify and understand novel therapeutic(s) NAbs in individuals lacking certain immune responses due to their poor endogenous production. Our results suggest a possible window of opportunity for administration of such NAbs when their full sequence becomes available. A method involving rapid deep RNA sequencing of patients infected with SARS-CoV-2 or its variants at the earliest infection time could help to develop personalized treatments using the identified specific NAbs.

Comparing media coverage of the pharmaceutical industry: pre-and post-pandemic lockdown

PurposeThe purpose of this paper is to analyze media coverage of the pharmaceutical industry before and after the COVID-19 lockdown to determine whether the coverage changed in light of a global health-care crisis and the fast-track development of vaccines and antiviral treatments. Design/methodology/approachThe top five US newspapers were audited, comparing the 12-month periods before and after March 2020 coinciding with the pandemic lockdown, yielding 493 front-page articles and editorials. Each headline and full-text article was separately analyzed and categorized as either positive, negative or neutral toward the pharmaceutical industry. A frequency analysis of the hot button issues covered in each article was conducted. FindingsYear 1 and Year 2 audit results were compared to identify changes in media coverage pre- and post-lockdown. The amount of coverage of the industry increased 145% and the tone of both headlines and articles shifted dramatically. Only one of the five newspapers had a net positive article rating of the industry pre-lockdown, four of five were net positive post-lockdown. The proportion of positive headlines increased 165%. The top issues discussed in the coverage shifted from persistent challenges for the industry (e.g. opioid crisis, high cost of drugs) to the emergence of the virus and status of vaccine development. Originality/valueThis research establishes how media coverage of the pharmaceutical industry changed as the industry responded to a global health-care crisis and identifies implications for industry stakeholders.

Multiple sclerosis and computational biology (Review).

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease whose prevalence has increased worldwide. The resultant symptoms may be debilitating and can substantially reduce the of patients. Computational biology, which involves the use of computational tools to answer biomedical questions, may provide the basis for novel healthcare approaches in the context of MS. The rapid accumulation of health data, and the ever-increasing computational power and evolving technology have helped to modernize and refine MS research. From the discovery of novel biomarkers to the optimization of treatment and a number of quality-of-life enhancements for patients, computational biology methods and tools are shaping the field of MS diagnosis, management and treatment. The final goal in such a complex disease would be personalized medicine, i.e., providing healthcare services that are tailored to the individual patient, in accordance to the particular biology of their disease and the environmental factors to which they are subjected. The present review article summarizes the current knowledge on MS, modern computational biology and the impact of modern computational approaches of MS.

Novel computational pipelines in antiviral structure­based drug design (Review).

Viral infections constitute a fundamental and continuous challenge for the global scientific and medical community, as highlighted by the ongoing COVID-19 pandemic. In combination with prophylactic vaccines, the development of safe and effective antiviral drugs remains a pressing need for the effective management of rare and common pathogenic viruses. The design of potent antivirals can be informed by the study of the three-dimensional structure of viral protein targets. Structure-based design of antivirals in silico provides a solution to the arduous and costly process of conventional drug development pipelines. Furthermore, rapid advances in high-throughput computing, along with the growth of available biomolecular and biochemical data, enable the development of novel computational pipelines in the hunt of antivirals. The incorporation of modern methods, such as deep-learning and artificial intelligence, has the potential to revolutionize the structure-based design and repurposing of antiviral compounds, with minimal side effects and high efficacy. The present review aims to provide an outline of both traditional computational drug design and emerging, high-level computing strategies.

Integrating Single Domain Antibodies into Field-Deployable Rapid Assays.

Single domain antibodies (sdAb) are the recombinant variable heavy domains derived from camelid heavy-chain antibodies. While they have binding affinities equivalent to conventional antibodies, sdAb are only one-tenth the size and possess numerous advantages such as excellent thermal stability with the ability to refold following denaturation, and inexpensive production in Escherichia coli or yeast. However, their small size does have drawbacks, one being that they can lose activity upon attachment or adsorption to surfaces, or may fail to adsorb efficiently, as they are highly soluble. This can make the transition from using conventional antibodies to sdAb nontrivial for assay development. Specifically, it is often necessary to re-optimize the protocols and tailor the recombinant sdAb through protein engineering to function efficiently in handheld assays, which currently are utilized for point of care testing and field applications. This work focuses on optimizing the integration of sdAb into rapid vertical flow assays. To achieve this goal, we engineered sdAb-based constructs and developed general protocols for the attachment of the sdAb to both gold nanoparticles and a support membrane. We achieved a limit of detection of 0.11 µg/mL for toxins staphylococcal enterotoxin B and ricin, both potential biothreat agents. Additionally, we demonstrated the ability to detect the nucleocapsid protein of SARS-CoV-2, a common target of antigen tests for COVID-19.

A CASE OF BORDETELLA BRONCHISEPTICA AND PNEUMOCYSTIS JIROVECI PNEUMONIA IN A YOUNG PATIENT

SESSION TITLE: Procedures in Chest Infections Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Pneumonia is a common condition that is seen in hospitals. Pneumocystis Jirovecii is an opportunist fungal pathogen. Bordetella bronchiseptica is a gram negative bacteria that causes infectious bronchitis in dogs and other animals, but rarely infects humans. CASE PRESENTATION: Patient is a 34 year old African American female with history of sickle cell trait, reported Lupus (not on treatment), asthma, COVID pneumonia who was admitted for worsening shortness of breath & productive cough with yellow sputum. She was previously hospitalized and discharged after being treated for Community-Acquired Pneumonia. In the ER, she was febrile, tachycardic, tachypneic, & hypoxic requiring BiPAP. CXR obtained showed findings concerning for multifocal pneumonia. Chest CT Angiogram was negative for PE. Patient was started on Vancomycin & Meropenem for treatment of her pneumonia. Blood cultures, Legionella, Strep pneumoniae, Aspergillus, Beta-D-glucan, Sputum culture, & MRSA screen were ordered for further evaluation of her infection. ANA screen reflex panel, lupus anticoagulant, anticardiolipin antibodies, beta-2 glycoprotein antibodies were also ordered given patient's reported history of SLE and the concern for SLE pneumonitis: ANA & Sjogren's Anti-SSA were positive;otherwise, autoimmune workup was unremarkable. During hospitalization, patient was eventually weaned down to nasal cannula and antibiotic was de-escalated to levaquin. However, sputum culture eventually grew Bordetella Bronchiseptica that was resistant to Levaquin so antibiotic regimen was switched to Doxycycline. In addition, Beta-D-glucan was noted to be elevated. Bronchoscopy was done for further evaluation;multiple transbronchial biopsies were positive Pneumocystis Jirovecii. Patient was then initiated on Bactrim for treatment of PJP Pneumonia along with a steroid taper. Patient was tested for HIV and it was negative. DISCUSSION: In this case, patient was found to have two rare pathogens, that are more common in immunocompromised patients such as those with HIV/AIDS, on high-dose corticosteroids or malignancy. This patient had a unconfirmed diagnosis of SLE and past COVID Pneumonia. Patient had Bordetella bronchiseptica pneumonia that is frequently isolated in the respiratory tract of animals but can cause severe respiratory infection in humans. This microorganism can cause upper respiratory tract infections, pneumonitis, endocarditis, peritonitis, meningitis, sepsis and recurrent bacteremia. Upon further discussion with the patient, she was found to have a recent pet dog. CONCLUSIONS: High level of clinical suspicious is needed in patient presenting with recurrent pneumonia with chest imaging findings suggestive of multifocal pneumonia. The mainstay of treatment for PJP is TMP-SMX and steroid. We recommend Fluoroquinolones or tetracycline for Bordetella bronchiseptica pneumonia. Reference #1: Benfield T, Atzori C, Miller RF, Helweg-Larsen J. Second-line salvage treatment of AIDS-associated Pneumocystis jirovecii pneumonia: a case series and systematic review. J Acquir Immune Defic Syndr. 2008 May 1;48(1):63-7. Reference #2: de la Fuente J, Albo C, Rodríguez A, Sopeña B, Martínez C. Bordetella bronchiseptica pneumonia in a patient with AIDS. Thorax. 1994 Jul;49(7):719-20. doi: 10.1136/thx.49.7.719. PMID: 8066571;PMCID: PMC475067. DISCLOSURES: No relevant relationships by Priya George No relevant relationships by ELINA MOMIN No relevant relationships by Mohammedumer Nagori

How to correct relative voxel scale factors for calculations of vector-difference Fourier maps in cryo-EM.

The atomic coordinates derived from cryo-electron microscopy (cryo-EM) maps can be inaccurate when the voxel scaling factors are not properly calibrated. Here, we describe a method for correcting relative voxel scaling factors between pairs of cryo-EM maps for the same or similar structures that are expanded or contracted relative to each other. We find that the correction of scaling factors reduces the amplitude differences of Fourier-inverted structure factors from voxel-rescaled maps by up to 20-30%, as shown by two cryo-EM maps of the SARS-CoV-2 spike protein measured at pH 4.0 and pH 8.0. This allows for the calculation of the difference map after properly scaling, revealing differences between the two structures for individual amino acid residues. Unexpectedly, the analysis uncovers two previously overlooked differences of amino acid residues in structures and their local structural changes. Furthermore, we demonstrate the method as applied to two cryo-EM maps of monomeric apo-photosystem II from the cyanobacteria Synechocystis sp. PCC 6803 and Thermosynechococcus elongatus. The resulting difference maps reveal many changes in the peripheral transmembrane PsbX subunit between the two species.

Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID.

About one out of eight people to convalesce from COVID-19 suffer from the so called Long COVID, a syndrome of non-specific symptoms with unclear pathogenesis. In a recent study published in Cell Long COVID participants reporting respiratory symptoms had low cortisol levels. In an as yet unpublished analysis from Yale University low plasma cortisol levels discriminated Long COVID from asymptomatic convalescent or healthy non-infected controls. Although various immune perturbations were present in Long COVID, low levels of cortisol were prominent and strikingly, depression and anxiety were increased. It has become clear that Long COVID features may be similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome, post-SARS sickness syndrome, and various chronic stress syndromes which have been linked to hypocortisolemia. Notably, lack of response of the hypothalamic-pituitary-adrenal axis to hypocortisolemia shows a suppressed axis in Long COVID. We suggest that the inability of hypothalamic-pituitary-adrenal axis to recover after the acute illness, perhaps due to protracted stress in predisposed individuals, may represent the pathogenetic basis of the Long COVID-associated clinical and immunological manifestations.