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.

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).

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]

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.

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.

The impact of COVID-19 during pregnancy on maternal and neonatal outcomes: a systematic review.

Several months after the onset of the epidemic, COVID-19 remains a global health issue. Scientific data on pregnancy, perinatal outcomes and vertical transmission of SARS-CoV-2 are constantly emerging but are still limited and unclear. The purpose of this systematic review was to summarize current evidence on vertical transmission rates, maternal, perinatal and neonatal outcomes and mode of delivery in pregnancies affected by COVID-19. An extensive search was conducted in PubMed, Google Scholar, Embase, and Scopus databases up to June 20, 2020. A total of 133 articles (51 case reports, 31 case series, 40 cohort studies and 2 case-control studies) reporting data from 8,092 subjects (6,046 pregnant women and 2,046 neonates) were considered eligible for inclusion in the systematic review. A substantial proportion of pregnant women with COVID-19 underwent caesarean section (case reports 82.2%, case series 74.2% and cohort studies 66.0%). Regarding vertical transmission, most neonates were tested negative (case reports 92.7%, case series studies 84.2%, cohort studies 97.1% and case control studies 100%). Maternal mortality rates ranged from 1% in cohort studies to 5.7% in case reports; neonatal mortality ranged from 2% in case reports to 3.3% in case series. Vertical transmission of SARS-CoV-2 from mother to child is rare. Careful screening of pregnant women seems important and specific guidelines with evidence-based decision algorithms for the mode of delivery in the context of a pregnancy affected by COVID-19 should be established.

COVID-19 features in children and adolescents: a systematic review and pooled analysis.

The purpose of the present study was to evaluate special features and probable correlations between symptoms, laboratory findings, treatment, and outcomes of COVID-19 in children and adolescents, through a systematic review and pooled analysis. Following database (Pubmed, Google Scholar, Scopus and Embase) search, forty articles were considered eligible identifying a total of 2,971 confirmed pediatric COVID-19 patients. Fever was reported in 55.1% of the cases, while 28.4% were asymptomatic. Radiological signs of pneumonia were observed in more than half of the cases and in 40.7% of asymptomatic patients. Fever showed the highest sensitivity (sensitivity: 60.3%, specificity: 48.8%), followed by cough (sensitivity: 47.4%, specificity: 76.7%), rhinorrhea (sensitivity: 21.1%, specificity: 88.4%) and diarrhea (sensitivity: 10.3%, specificity: 88.4%), in differentiating cases with positive radiological signs for pneumonia. Compared to school age children, preschoolers (adjusted OR=6.01, 95%CI: 1.73-20.91) were more prone to pneumonia findings. Various combinations of treatments were used across studies, without following any strict guidelines. Most children (>90%) had full recovery and rarely presented complications. Fever seems to be the most frequent symptom in pediatric COVID-19, but pediatricians should additionally evaluate cough, rhinorrhea, and diarrhea as indicators of SARS-CoV-2 infection. Asymptomatic cases were common, but not the majority, and a significant percentage had developed radiologic findings of pneumonia. Thorough reassessment of treatment and management guidelines should be helpful.

Could COVID-19's Aftermath on Children's Health Be Felt into the 22nd Century?

The COVID-19 pandemic has massively affected people's health, societies, and the global economy. Our lives are no longer as they were before COVID-19, and, most likely, will never be the same again. We hypothesize that the effect of the COVID-19 pandemic on population health and the economy will last for a very long time and will still be felt in the 22nd century. Our hypothesis is based on evidence from the 1918-1919 influenza pandemic, the Dutch famine during the Second World War, and the 2007-2008 economic crisis, as well as from the rationally predicted impact of COVID-19 on human development. We expect that the COVID-19 pandemic, including the mitigation measures taken against it, will affect children's development in multiple ways, including obesity, both while in utero and during critical and sensitive windows of development, including the early childhood years and those of puberty and adolescence. The psychosocial and biological impact of this effect will be considerable and unequally distributed. The implications will last at least a lifetime, and, through inter-generational transmission, will likely take us to future generations, into the 22nd century. We argue for the urgent need of designing and initiating comprehensive longitudinal cohort studies to closely monitor the long-term effects of COVID-19 on children conceived, born, and raised during the pandemic. Such an approach requires a close and effective collaboration between scientists, healthcare providers, policymakers, and the younger generations, and it will hopefully uncover evidence necessary to understand and mitigate the impact of the pandemic on people's lives in the 21st and 22nd centuries.

Thrombocytopenia in COVID­19 and vaccine­induced thrombotic thrombocytopenia.

The highly heterogeneous symptomatology and unpredictable progress of COVID­19 triggered unprecedented intensive biomedical research and a number of clinical research projects. Although the pathophysiology of the disease is being progressively clarified, its complexity remains vast. Moreover, some extremely infrequent cases of thrombotic thrombocytopenia following vaccination against SARS­CoV­2 infection have been observed. The present study aimed to map the signaling pathways of thrombocytopenia implicated in COVID­19, as well as in vaccine­induced thrombotic thrombocytopenia (VITT). The biomedical literature database, MEDLINE/PubMed, was thoroughly searched using artificial intelligence techniques for the semantic relations among the top 50 similar words (>0.9) implicated in COVID­19­mediated human infection or VITT. Additionally, STRING, a database of primary and predicted associations among genes and proteins (collected from diverse resources, such as documented pathway knowledge, high­throughput experimental studies, cross­species extrapolated information, automated text mining results, computationally predicted interactions, etc.), was employed, with the confidence threshold set at 0.7. In addition, two interactomes were constructed: i) A network including 119 and 56 nodes relevant to COVID­19 and thrombocytopenia, respectively; and ii) a second network containing 60 nodes relevant to VITT. Although thrombocytopenia is a dominant morbidity in both entities, three nodes were observed that corresponded to genes (AURKA, CD46 and CD19) expressed only in VITT, whilst ADAM10, CDC20, SHC1 and STXBP2 are silenced in VITT, but are commonly expressed in both COVID­19 and thrombocytopenia. The calculated average node degree was immense (11.9 in COVID­19 and 6.43 in VITT), illustrating the complexity of COVID­19 and VITT pathologies and confirming the importance of cytokines, as well as of pathways activated following hypoxic events. In addition, PYCARD, NLP3 and P2RX7 are key potential therapeutic targets for all three morbid entities, meriting further research. This interactome was based on wild­type genes, revealing the predisposition of the body to hypoxia­induced thrombosis, leading to the acute COVID­19 phenotype, the 'long­COVID syndrome', and/or VITT. Thus, common nodes appear to be key players in illness prevention, progression and treatment.

Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations.

PURPOSE: The beneficial effect of glucocorticoids in coronavirus disease (COVID-19) is established, but whether adrenal cortisol secretion is impaired in COVID-19 is not fully elucidated. In this case-control study, we investigated the diurnal free bioavailable salivary cortisol secretion in COVID-19 patients. METHODS: Fifty-two consecutive COVID-19 patients-before dexamethasone treatment in cases required-recruited between April 15 to June 15, 2021, (NCT04988269) at Laikon Athens University-Hospital, and 33 healthy age- and sex-matched controls were included. Diurnal salivary cortisol (8 a.m., 12, 6, and 10 p.m.), plasma adrenocorticotropin (ACTH) and aldosterone, and serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were assessed. Diurnal salivary dehydroepiandrosterone (DHEA) and IL-6 were also assessed in subgroups of patients. RESULTS: Median CRP and IL-6 measurements were about sixfold higher in patients than controls (both p < 0.001) Morning salivary cortisol levels did not differ between the two groups, but patients exhibited higher median levels of evening and nocturnal salivary cortisol compared to controls [0.391 (0.054, 0663) vs. 0.081 (0.054, 0.243) µg/dl, p < 0.001 and 0.183 (0.090, 0.834) vs. 0.054 (0.054, 0.332) µg/dl, p < 0.001, respectively], resulting in higher time-integrated area under the curve (AUC) (4.81 ± 2.46 vs. 2.75 ± 0.810, respectively, p < 0.001). Circulating ACTH, DHEA, and aldosterone levels were similar in patients and controls. Serum IL-6, but not ACTH levels, was strongly correlated with nocturnal cortisol salivary levels (ρ = 0.555, p < 0.001) in patients. CONCLUSIONS: Increased evening and nocturnal but not morning cortisol secretion may occur in even clinically mild COVID-19. In the context of acute viral infection (COVID-19), IL-6 may partially replace ACTH as a stimulus of the glucocorticoid-secreting adrenal zona-fasciculata without influencing the secretion of DHEA and aldosterone. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04988269?term=yavropoulou&draw=2&rank=3 (NCT04988269).

Angiotensin-Converting Enzyme 2 (ACE2) As a Novel Biorecognition Element in A Cell-Based Biosensor for the Ultra-Rapid, Ultra-Sensitive Detection of the SARS-CoV-2 S1 Spike Protein Antigen

Antigen screening for the SARS-CoV-2 S1 spike protein is among the most promising tools for the mass monitoring of asymptomatic carriers of the virus, especially in limited resource environments. Herewith, we report on the possible use of the angiotensin-converting enzyme 2 (ACE2), the natural receptor and entry point of the virus, as a biorecognition element for the detection of the S1 antigen combined with an established bioelectric biosensor based on membrane-engineered cells. The working principle of our approach is based on the measurable change of the electric potential of membrane-engineered mammalian cells bearing ACE2 after attachment of the respective viral protein. We demonstrate that sensitive and selective detection of the S1 antigen is feasible in just three min, with a limit of detection of 20 fg/mL. In a preliminary clinical application, positive patient-derived samples were identified with a 87.9% score compared to RT-PCR. No cross-reactivity was observed against a wide range of nucleocapsid protein concentrations. The novel biosensor is embedded in a commercially ready-to-use testing platform, complete with the consumable immobilized cell–electrode interface and a portable read-out device operable through smartphone or tablet. In addition, the possible application of the system for the high throughput screening of potential pharmacological inhibitors of the ACE2 receptor-S1 RBD interaction is discussed.

Haematological malignancies implications during the times of the COVID-19 pandemic.

The COVID-19 pandemic has complicated current healthcare services for cancer patients. Patients with haematological malignancies specifically seem vulnerable to SARS-CoV-2 infection due to their immunosuppressed status. The COVID-19 pandemic influences every step of the assessment and treatment of a haematological malignancy. Clinicians must adhere to strict policies to not spread the virus to their patients while they must also adjust their workflow for maximum productivity. These difficulties accentuate the ever-present need to improve the healthcare services for cancer patients. This improvement is needed not only to combat the problems that arose from the COVID-19 pandemic but also to establish a framework for the management of patients with haematological malignancies in potential future pandemics.

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS.

Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs' findings, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic-pituitary-adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings.

Inherited/Genetically-Associated Pheochromocytoma/ Paraganglioma Syndromes and COVID-19.

In some subjects with inherited pheochromocytoma/paraganglioma (PPG) syndromes, hypoxia-inducible factor 1 alpha (HIF1α) stabilization/activation could lead to an increase in angiotensin converting enzymes (ACE). This would result in the stimulation of angiotensin (AT) II production and, hence, reduce the availability of ACE 2. The latter would provide decreased numbers of binding sites for the spike protein of SARS-CoV-2 and, therefore, result in less points of viral entry into cells. Thus, subjects with HIF1α-associated PPG syndromes may benefit from an inherent protective effect against COVID-19. Such an implication of HIF1α vis-à-vis COVID-19 could open ways of therapeutic interventions.

Clinical Application of the Novel Cell-Based Biosensor for the Ultra-Rapid Detection of the SARS-CoV-2 S1 Spike Protein Antigen: A Practical Approach.

The availability of antigen tests for SARS-CoV-2 represents a major step for the mass surveillance of the incidence of infection, especially regarding COVID-19 asymptomatic and/or early-stage patients. Recently, we reported the development of a Bioelectric Recognition Assay-based biosensor able to detect the SARS-CoV-2 S1 spike protein expressed on the surface of the virus in just three minutes, with high sensitivity and selectivity. The working principle was established by measuring the change of the electric potential of membrane-engineered mammalian cells bearing the human chimeric spike S1 antibody after attachment of the respective viral protein. In the present study, we applied the novel biosensor to patient-derived nasopharyngeal samples in a clinical set-up, with absolutely no sample pretreatment. More importantly, membrane-engineered cells were pre-immobilized in a proprietary biomatrix, thus enabling their long-term preservation prior to use as well as significantly increasing their ease-of-handle as test consumables. The plug-and-apply novel biosensor was able to detect the virus in positive samples with a 92.8% success rate compared to RT-PCR. No false negative results were recorded. These findings demonstrate the potential applicability of the biosensor for the early, routine mass screening of SARS-CoV-2 on a scale not yet realized.

Lamotrigine Reduces Stress Symptoms of Chronic Anxiety in the Times of the Covid-19 Natural Catastrophe-A Case Report.

The SARS-CoV-2 pandemic has been a worldwide chronic, stress-inducing natural catastrophe associated with increased emotional challenging. Patients with Post-traumatic stress disorder (PTSD), self-injury behavior, and obesity are predisposed to aggravation of their symptoms at this time, requiring new therapeutic approaches to balance their disrupted neuro-hormonal stress axis. Here we present our observations of an off-label treatment with lamotrigine in an adolescent girl with PTSD, self-injury behavior, and obesity. Lamotrigine was an efficacious pharmaceutical intervention that helped the patient deal with chronic stress and associated anxiety. The results are discussed based on our previous basic research outcomes in animals and humans that focused on the glutamate-cortisol circuits within the limbic brain.

Self-reported changes in anxiety, depression and suicidality during the COVID-19 lockdown in Greece.

INTRODUCTION: There are only a few published empirical data on COVID-19's effects on the mental health. MATERIAL AND METHODS: During lockdown, an online questionnaire registered demographic, health data, previous psychiatric history, current anxiety, depression and suicidality, believing in conspiracy theories and other domains. Data from 3399 persons were used (81.08% females; aged 34.02 ± 9.72 and 18.27% males; aged 36.38±10.33). Distress and clinical depression were identified with the use of cut-off and a previously developed algorithm respectively. STATISTICAL ANALYSIS: A post-stratification method was used; descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses and Factorial Analysis of Variance (ANOVA) tested relations among variables. RESULTS: Clinical depression was present in 9.31% of the stratified sample, while 8.5% had severe distress; increased anxiety was present in more than 45%. Suicidal thoughts increased in 10.40% and decreased in 4.42%. Beliefs in conspiracy theories were widely prevalent; at least half of cases were following various misconceptions. A model for the development of depression was created with general health status, previous history of depression, self-harm and suicidal attempts, family responsibility, economic change, and age acting as risk factors, while keeping a daily routine, pursuing religiousness/spirituality, and believing in conspiracy theories acting as protective factors. CONCLUSIONS: The model developed here revealed multiple vulnerabilities and an interplay leading from simple anxiety to clinical depression and suicidality through distress. This could be of practical utility since most of these factors are modifiable. Future research, as well as interventions, should focus specifically on them.