Decreased Gas6 and sAxl Plasma Levels Are Associated with Hair Loss in COVID-19 Survivors.

Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96-0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45-4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92-0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97-1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39-12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge.

Pathway and Network Analyses Identify Growth Factor Signaling and MMP9 as Potential Mediators of Mitochondrial Dysfunction in Severe COVID-19.

Patients with preexisting metabolic disorders such as diabetes are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Mitochondrion, the very organelle that controls cellular metabolism, holds the key to understanding disease progression at the cellular level. Our current study aimed to understand how cellular metabolism contributes to COVID-19 outcomes. Metacore pathway enrichment analyses on differentially expressed genes (encoded by both mitochondrial and nuclear deoxyribonucleic acid (DNA)) involved in cellular metabolism, regulation of mitochondrial respiration and organization, and apoptosis, was performed on RNA sequencing (RNASeq) data from blood samples collected from healthy controls and patients with mild/moderate or severe COVID-19. Genes from the enriched pathways were analyzed by network analysis to uncover interactions among them and up- or downstream genes within each pathway. Compared to the mild/moderate COVID-19, the upregulation of a myriad of growth factor and cell cycle signaling pathways, with concomitant downregulation of interferon signaling pathways, were observed in the severe group. Matrix metallopeptidase 9 (MMP9) was found in five of the top 10 upregulated pathways, indicating its potential as therapeutic target against COVID-19. In summary, our data demonstrates aberrant activation of endocrine signaling in severe COVID-19, and its implication in immune and metabolic dysfunction.

Predictive model for BNT162b2 vaccine response in cancer patients based on blood cytokines and growth factors.

Background: Patients with cancer, especially hematological cancer, are at increased risk for breakthrough COVID-19 infection. So far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed. Methods: We employed machine learning approaches to identify a biomarker signature based on blood cytokines, chemokines, and immune- and non-immune-related growth factors linked to vaccine immunogenicity in 199 cancer patients receiving the BNT162b2 vaccine. Results: C-reactive protein (general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) correctly classified patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments. Conclusion: We propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at persistent high risk of COVID-19 despite vaccination with BNT162b2. Our data also suggest that such a signature may reflect the inherent immunological constitution of some cancer patients who are refractive to immunotherapy.

[Neurological disorders in the postcovid period]. / Nevrologicheskie narusheniya v postkovidnom periode.

The consequences of COVID-19 include a wide range of neurological, emotional and cognitive impairments. The pathogenesis of postcovid disorders is complex and has not been fully studied. The article discusses the pathogenesis and clinical manifestations of neuropostocoid. A hypothesis is formulated about the possible role of circumventricular organs in its formation. The main directions of treatment of patients with postcovid disorders are proposed.

Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases.

The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.

Chemerin plasma levels are increased in COVID-19 patients and are an independent risk factor of mortality.

Background: Chemerin is an extracellular protein with chemotactic activities and its expression is increased in various diseases such as metabolic syndrome and inflammatory conditions. Its role in lung pathology has not yet been extensively studied but both known pro- and anti-inflammatory properties have been observed. The aim of our study was to evaluate the involvement of the chemerin/ChemR23 system in the physiopathology of COVID-19 with a particular focus on its prognostic value. Methods: Blood samples from confirmed COVID-19 patients were collected at day 1, 5 and 14 from admission to Erasme Hospital (Brussels - Belgium). Chemerin concentrations and inflammatory biomarkers were analyzed in the plasma. Blood cells subtypes and their expression of ChemR23 were determined by flow cytometry. The expression of chemerin and ChemR23 was evaluated on lung tissue from autopsied COVID-19 patients by immunohistochemistry (IHC). Results: 21 healthy controls (HC) and 88 COVID-19 patients, including 40 in intensive care unit (ICU) were included. Plasma chemerin concentration were significantly higher in ICU patients than in HC at all time-points analyzed (p<0.0001). Moreover, they were higher in deceased patients compared to survivors (p<0.05). Logistic univariate regression and multivariate analysis demonstrated that chemerin level at day 14 of admission was an independent risk factor for death. Accordingly, chemerin levels correlated with inflammatory biomarkers such as C-reactive protein and tumor necrosis factor α. Finally, IHC analysis revealed a strong expression of ChemR23 on smooth muscle cells and chemerin on myofibroblasts in advanced acute respiratory distress syndrome (ARDS). Discussion: Increased plasma chemerin levels are a marker of severity and may predict death of COVID-19 patients. However, multicentric studies are needed, before chemerin can be considered as a biomarker of severity and death used in daily clinical practice. Further studies are also necessary to identify the precise mechanisms of the chemerin/ChemR23 system in ARDS secondary to viral pneumonia.

Endocytic trafficking of GAS6-AXL complexes is associated with sustained AKT activation.

AXL, a TAM receptor tyrosine kinase (RTK), and its ligand growth arrest-specific 6 (GAS6) are implicated in cancer metastasis and drug resistance, and cellular entry of viruses. Given this, AXL is an attractive therapeutic target, and its inhibitors are being tested in cancer and COVID-19 clinical trials. Still, astonishingly little is known about intracellular mechanisms that control its function. Here, we characterized endocytosis of AXL, a process known to regulate intracellular functions of RTKs. Consistent with the notion that AXL is a primary receptor for GAS6, its depletion was sufficient to block GAS6 internalization. We discovered that upon receptor ligation, GAS6-AXL complexes were rapidly internalized via several endocytic pathways including both clathrin-mediated and clathrin-independent routes, among the latter the CLIC/GEEC pathway and macropinocytosis. The internalization of AXL was strictly dependent on its kinase activity. In comparison to other RTKs, AXL was endocytosed faster and the majority of the internalized receptor was not degraded but rather recycled via SNX1-positive endosomes. This trafficking pattern coincided with sustained AKT activation upon GAS6 stimulation. Specifically, reduced internalization of GAS6-AXL upon the CLIC/GEEC downregulation intensified, whereas impaired recycling due to depletion of SNX1 and SNX2 attenuated AKT signaling. Altogether, our data uncover the coupling between AXL endocytic trafficking and AKT signaling upon GAS6 stimulation. Moreover, our study provides a rationale for pharmacological inhibition of AXL in antiviral therapy as viruses utilize GAS6-AXL-triggered endocytosis to enter cells.

Preliminary investigation of gene expression levels of PAPP-A, STC-2, and HIF-1α in SARS-Cov-2 infected patients.

BACKGROUND: Coronavirus-19 is still considered a pandemic that influences the world. Other molecular alterations should be clearer besides the increasing cytokine storm and pro-inflammatory molecules. Hypoxic conditions that induce HIF-1α lead to stimulate gene expression of STC-2 that targets PAPP-A expression. This study aimed to determine gene expression levels of PAPP-A, STC-2, and HIF-1α in COVID-19 infection. We also aimed to reveal the relationship of these genes with laboratory and clinical data of COVID-19 patients. MATERIALS AND RESULTS: We extracted RNA from peripheral blood samples of COVID-19(+) and COVID-19(-) individuals. The real-time PCR method was used to measure mRNA expression of PAPP-A, STC-2, and HIF-1α. Gene expression analysis was evaluated by the 2-ΔΔCt method. PAPP-A, STC-2, and HIF-1α mRNA expressions of severe patients were higher than healthy individuals (p = 0.0451, p = 0.4466, p < 0.0001, respectively). Correlation analysis of gene expression patterns of severe patients demonstrated a positive correlation between PAPP-A and STC-2 (p < 0.0001, r = 0.8638). CONCLUSION: This is the first study that investigates the relation of PAPP-A, STC-2, and HIF-1α gene expression in patients with COVID-19 infection. Besides the routine laboratory findings, PAPP-A, STC-2, and HIF-1α mRNA expressions may be considered to patients' prognosis as a sign of increased cytokines and pro-inflammatory molecules.

Baseline Plasma Gas6 Protein Elevation Predicts Adverse Outcomes in Hospitalized COVID-19 Patients.

Reliable biomarkers allowing early patients' stratification for the risk of adverse outcomes in COVID-19 are lacking. Gas6, together with its tyrosine kinase receptors named TAM, is involved in the regulation of immune homeostasis, fibrosis, and thrombosis. Our aim was to evaluate whether Gas6, sAxl, and sMerTK could represent early predictors of disease evolution either towards a negative (death or need of ICU admission) or a positive (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. To this purpose, between January and May 2021 (corresponding to third pandemic wave in Italy), 139 consecutive SARS-CoV-2 positive patients were enrolled in a prospective observational study. Plasma levels of these molecules were measured by ELISA at the time of hospitalization and after 7 and 14 days. We observed that higher plasma Gas6 concentrations at hospital admission were associated with a worsening in clinical conditions while lower sMerTK concentrations at baseline and after 7 days of hospitalization were associated with a more favorable outcome. At multivariate analysis, after correction for demographic and COVID-19 severity variables (NEWS2 and PiO2/FiO2), only Gas6 measured at baseline predicted an adverse prognosis with an odds ratio of 1.03 (C.I. 1.01-10.5). At ROC curve analysis, baseline Gas6 levels higher than 58.0 ng/ml predicted a severe disease evolution with 53.3% sensitivity and 77.6% specificity (area under the curve 0.653, p = 0.01, likelihood ratio of 2.38, IQR: 1.46-3.87). Taken together, these results support the hypothesis that a dysregulation in the Gas6/TAM axis could play a relevant role in modulating the course of COVID-19 and suggest that plasma Gas6 may represent a promising prognostic laboratory parameter for this condition.

Nanocurcumin Potently Inhibits SARS-CoV-2 Spike Protein-Induced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial Cells.

Interleukin-mediated deep cytokine storm, an aggressive inflammatory response to SARS-CoV-2 virus infection in COVID-19 patients, is correlated directly with lung injury, multi-organ failure, and poor prognosis of severe COVID-19 patients. Curcumin (CUR), a phenolic antioxidant compound obtained from turmeric (Curcuma longa L.), is well-known for its strong anti-inflammatory activity. However, its in vivo efficacy is constrained due to poor bioavailability. Herein, we report that CUR-encapsulated polysaccharide nanoparticles (CUR-PS-NPs) potently inhibit the release of cytokines, chemokines, and growth factors associated with damage of SARS-CoV-2 spike protein (CoV2-SP)-stimulated liver Huh7.5 and lung A549 epithelial cells. Treatment with CUR-PS-NPs effectively attenuated the interaction of ACE2 and CoV2-SP. The effects of CUR-PS-NPs were linked to reduced NF-κB/MAPK signaling which in turn decreased CoV2-SP-mediated phosphorylation of p38 MAPK, p42/44 MAPK, and p65/NF-κB as well as nuclear p65/NF-κB expression. The findings of the study strongly indicate that organic NPs of CUR can be used to control hyper-inflammatory responses and prevent lung and liver injuries associated with CoV2-SP-mediated cytokine storm.

Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein in inflammation and tumor immunity.

Human Interleukin-18 (IL-18) is an omnipresent proinflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases and serves as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase of COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18-Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors are highly desirable; however, the structure of human IL-18BP in complex with IL-18 has been elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP toward IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecules from different complexes, resulting in a novel tetramer with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings provide a framework for innovative, structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease.

The Impact of mRNA Technology in Regenerative Therapy: Lessons for Oral Tissue Regeneration.

Oral tissue regeneration following chronic diseases and injuries is limited by the natural endogenous wound-healing process. Current regenerative approaches implement exogenous systems, including stem cells, scaffolds, growth factors, and plasmid DNA/viral vectors, that induce variable clinical outcomes. An innovative approach that is safe, effective, and inexpensive is needed. The lipid nanoparticle-encapsulated nucleoside-modified messenger RNA (mRNA) platform has proven to be a successful vaccine modality against coronavirus disease 2019, demonstrating safety and high efficacy in humans. The same fundamental technology platform could be applied to facilitate the development of mRNA-based regenerative therapy. While the platform has not yet been studied in the field of oral tissue regeneration, mRNA therapeutics encoding growth factors have been evaluated and demonstrated promising findings in various models of soft and hard tissue regeneration such as myocardial infarction, diabetic wound healing, and calvarial and femoral bone defects. Because restoration of both soft and hard tissues is crucial to oral tissue physiology, this new therapeutic modality may help to overcome challenges associated with the reconstruction of the unique and complex architecture of oral tissues. This review discusses mRNA therapeutics with an emphasis on findings and lessons in different regenerative animal models, and it speculates how we can apply mRNA-based platforms for oral tissue regeneration.

[Determination of the prevalence of postcovid syndrome and assessment of the effectiveness of the drug Cortexin in the treatment of neurological disorders in patients with postcovid syndrome. Results of the multicenter clinical and epidemiological observational program CORTEX]. / Opredelenie rasprostranennosti postkovidnogo sindroma i otsenka effektivnosti preparata Korteksin v terapii nevrologicheskikh narushenii u patsientov s postkovidnym sindromom. Rezul'taty mnogotsentrovoi nablyudatel'noi programmy KORTEKS.

OBJECTIVE: To study the prevalence of clinical manifestations of postcoid syndrome in patients at an outpatient neurological appointment, to evaluate the effectiveness of therapy regimens using Cortexin at doses of 10 mg and 20 mg IM for 10 days. MATERIALS AND METHODS: 674 neurologists from all regions of the Russian Federation, Azerbaijan, Kyrgyzstan and Kazakhstan took part in the study. A total of 979 COVID-19 patients were recruited. The average age is 54.6±0.45 years. The duration of the transferred SARS-CoV-2 days and from 1 month or more 12. 3 visits were carried out: 1 on the day of treatment (assessment of complaints, analysis of scale indicators, prescription of the drug Cortexin in doses of 10-20 mg/m for 10 days). 2 (telephone survey) visit for 10-14 days, 3 visit - for 30 days at the reception. The condition was assessed using the Asthenia Assessment Scale (MFI-20), the Brief Mental Status Assessment Scale (MMSE questionnaire), the Schulte test, and the Subjective Treatment Quality Assessment Scale. RESULTS: The daily proportion of patients with complaints after a previous coronavirus infection was 30% in the total structure of neurological admission. The most common complaints: fatigue, general weakness, decreased memory and concentration, dizziness, sleep disturbance, irritability, aggression, shortness of breath, pain syndromes, excessive sweating, anosmia, hyposmia, perverted taste of paresthesia, hair loss, blurred vision, unstable blood pressure, tachycardia, allergic reactions, menstrual irregularities, erectile dysfunction, apathy, panic attacks, suicidal thoughts, depression, refusal to eat meat. CONCLUSION: There was no significant correlation of clinical symptoms with the severity of COVID-19, the percentage of lung tissue damage, and different periods of postcovid syndrome. The clinical efficacy of the drug Cortexin in dosages of 10 and 20 mg for the correction of cognitive and asthenic disorders has been proven. Revealed anti-anxiety, antidepressant and anxiolytic activity of Cortexin is more pronounced when using a dosage of 20 mg.

Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway.

Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection.Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; ACTB: ß-actin; ATF: activating transcription factor; ATG: autophagy-related; BafA1: bafilomycin A₁; BDBV: Bundibugyo ebolavirus; CALR: calreticulin; CANX: calnexin; CHX: cycloheximide; CMA: chaperone-mediated autophagy; ConA: concanamycin A; CRISPR: clusters of regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; dsRNA: double-stranded RNA; EBOV: Zaire ebolavirus; EDEM: ER degradation enhancing alpha-mannosidase like protein; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; Env: envelope glycoprotein; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GP: glycoprotein; HA: hemagglutinin; HDAC6: histone deacetylase 6; HMM: high-molecular-mass; HIV-1: human immunodeficiency virus type 1; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IAV: influenza A virus; IP: immunoprecipitation; KIF: kifenesine; Lac: lactacystin; LAMP: lysosomal associated membrane protein; MAN1B1/ERManI: mannosidase alpha class 1B member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARV: Marburg virus; MLD: mucin-like domain; NHK/SERPINA1: alpha1-antitrypsin variant null (Hong Kong); NTZ: nitazoxanide; PDI: protein disulfide isomerase; RAVV: Ravn virus; RESTV: Reston ebolavirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SBOV: Sudan ebolavirus; sGP: soluble GP; SQSTM1/p62: sequestosome 1; ssGP: small soluble GP; TAFV: Taï Forest ebolavirus; TIZ: tizoxanide; TGN: thapsigargin; TLD: TXN (thioredoxin)-like domain; Ub: ubiquitin; UPR: unfolded protein response; VLP: virus-like particle; VSV: vesicular stomatitis virus; WB: Western blotting; WT: wild-type; XBP1: X-box binding protein 1.

Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19.

BACKGROUND: The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. OBJECTIVES: We aimed to investigate the effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1ß, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1ß (MIP-1ß), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. RESULTS: The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. CONCLUSIONS: The findings do not support the use of a single dose of 200,000 IU vitamin D3, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19.This trial was registered at clinicaltrials.gov as NCT04449718.

Efficacy of QR678 Neo® hair growth factor formulation for the treatment of hair loss in Covid-19-induced persistent Telogen Effluvium-A prospective, clinical, single-blind study.

BACKGROUND: Telogen Effluvium (TE) in a post-Covid-19 patient causes excessive shedding of hair. No definite treatment is available till now. Past studies demonstrates that QR678Neo® has shown promising results in various types of Alopecia. AIM: In this study, we aim to establish efficacy of QR678 Neo® hair growth factor formulation administration in Covid-19-induced persistent TE for treatment of hair loss and for hair regrowth. MATERIAL & METHOD: Twenty adult patients (all females) presenting with persistent TE starting few weeks after recovery from Covid-19 infection, and continuing beyond 6 months were included for the study. A 1.5 mL solution of QR678 Neo® hair growth factor formulation was administered in the scalp per session. A total of 8 sessions (one session every 4 weeks) were done. The results were assessed at the baseline, after 4thsession, and 1 month after 8th session. RESULTS: Most of the patients showed significant reduction in hair fall; 89% patients showed excellent hair growth. Global photographic assessment score showed marked improvement, which maintained even post therapy. Videomicroscopic assessment showed increase in the hair count (mean =29.32) after 8th session, that further improved even post therapy. The subjective assessment scores for overall hair growth, appearance of hair, reduction in visibility of the scalp, and hair loss were 4, 4.5, 4.25, and 5, respectively. CONCLUSION: Management of Covid-19-induced persistent Telogen Effluvium has been unclear and futile so far. Intra-dermal administration of QR678 Neo® hair growth factor formulation in the scalp, reduces hair fall, improves hair regrowth, and increases the hair density.

BPIFB4 Circulating Levels and Its Prognostic Relevance in COVID-19.

Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people.

Immediate Pre-Partum SARS-CoV-2 Status and Immune Profiling of Breastmilk: A Case-Control Study.

Objetive: To address the prevalence of SARS-CoV-2 and the evolutionary profile of immune compounds in breastmilk of positive mothers according to time and disease state. Methods: Forty-five women with term pregnancies with confirmed non-severe SARS-CoV-2 infection (case group), and 96 SARS-CoV-2 negative women in identical conditions (control group) were approached, using consecutive sample. Weekly (1st to 5th week postpartum) reverse transcription polymerase chain reaction (RT-PCR) in nasopharyngeal swabs (cases) and breastmilk (cases and controls) were obtained. Concentration of cytokines, chemokines, and growth factors in breastmilk (cases and controls) were determined at 1st and 5th week post-partum. Results: Thirty-seven (study group) and 45 (control group) women were enrolled. Symptomatic infection occurred in 56.8% of women in the study group (48% fever, 48% anosmia, 43% cough). SARS-CoV-2 RNA was not found in breastmilk samples. Concentrations of cytokines (IFN-γ, IL-1ra, IL-4, IL-6, IL-9, IL-13, and TNF-α) chemokines (eotaxin, IP-10, MIP-1α, and RANTES) and growth factors (FGF, GM-CSF, IL7, and PDGF-BB) were higher in breastmilk of the study compared with the control group at 1st week postpartum. Immune compounds concentrations decreased on time, particularly in the control group milk samples. Time of nasopharyngeal swab to become negative influenced the immune compound concentration pattern. Severity of disease (symptomatic or asymptomatic infection) did not affect the immunological profile in breast milk. Conclusions: This study confirms no viral RNA and a distinct immunological profile in breastmilk according to mother's SARS-CoV-2 status. Additional studies should address whether these findings indicate efficient reaction against SARS-CoV-2 infection, which might be suitable to protect the recipient child.

Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients.

Coronavirus disease 19 (COVID-19) presents with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels and evolution of the damage associated molecular patterns (DAMPS) cell free DNA (cfDNA), extracellular histone H3 (H3) and neutrophil elastase (NE), and the immune modulators GAS6 and AXL in relation to clinical parameters, ICU scoring systems and mortality in patients (n = 100) with severe COVID-19. cfDNA, H3, NE, GAS6 and AXL were increased in COVID-19 patients compared to controls. These measures associated with occurrence of clinical events and intensive care unit acquired weakness (ICUAW). cfDNA and GAS6 decreased in time in patients surviving to 30 days post ICU admission. A decrease of 27.2 ng/mL cfDNA during ICU stay associated with patient survival, whereas levels of GAS6 decreasing more than 4.0 ng/mL associated with survival. The presence of H3 in plasma was a common feature of COVID-19 patients, detected in 38% of the patients at ICU admission. NETosis markers cfDNA, H3 and NE correlated well with parameters of tissue damage and neutrophil counts. Furthermore, cfDNA correlated with lowest p/f ratio and a lowering in cfDNA was observed in patients with ventilator-free days.