Psychosomatic state and laboratory parameters of COVID-19 convalescent patients.

Objective. To evaluate some parameters of the psychosomatic state, cytokine levels (IL-6, IL-8, IL-17A), and free radical status (levels of nitrates and nitrites, antioxidant plasma activity) in convalescent patients after severe COVID-19. Patients and methods. We examined 64 patients who had severe COVID-19 and underwent either a 30-35-day course of inpatient rehabilitation after their discharge from a hospital for infectious diseases or a 60-65-day course of outpatient rehabilitation at the Ambulatory Center of Nalchik, Clinical Hospital No 1. Results. We surveyed patients after severe COVID-19 and found that they required a long rehabilitation. Many of them reported asthenic syndrome, psycho-emotional disorders, and other complaints upon discharge from the hospital. Serum levels of proinflammatory cytokines remained high in patients after severe COVID-19 even 30-35 days following their discharge (p < 0.05). Serum levels of IL-6, IL-8, nitrites, and nitrates remained elevated on days 60-65 following discharge (p < 0.05), despite comprehensive therapy in a rehabilitation department. Plasma antioxidant activity was reduced, whereas IL-17A level normalized by this time. Conclusion. Our findings suggest that currently used rehabilitation measures for COVID-19 are insufficient. Adequate rehabilitation of convalescent COVID-19 patients requires proper monitoring of their immune system condition, as well as new effective methods for immune correction and restoration of their psychoemotional status after the acute phase of the disease.Copyright © 2022, Dynasty Publishing House. All rights reserved.

BRAIN AND BEHAVIOR PREDICTORS OF SARS-CoV-2 INFECTION AMONG PEOPLE WITH HIV

Background: Recent findings from the UK Biobank revealed that healthy adults who later became infected with SARS-CoV-2 had lower brain volumes in regions involved in risk-taking behavior and olfaction compared to individuals who did not become infected. We examined if similar pre-existing differences in brain regions correspond to SARS-CoV-2 infection among people with HIV (PWH) receiving suppressive ART. Method(s): Participants included adult Thai MSM enrolled in the acute HIV (AHI) cohort (RV254/SEARCH010) in Bangkok, Thailand. Participants underwent 3T MRI and clinical assessments (i.e., HIV disease metrics, cognitive testing, and self-reported mood and substance use). ART initiation occurred within 5 days of the MRI (median=same day). Regional brain volumes were summed across hemispheres and corrected for head size. Brain volumes and clinical indices were compared between participants with laboratory confirmed SARS-CoV-2 and those without a diagnosis of SARS-CoV-2 following ART initiation. Machine learning was utilized to identify variables at the time of enrollment into the cohort that predicted subsequent SARS-CoV-2 infection status. Result(s): 112 participants were included in the analysis. All study participants achieved viral suppression after ART and received SARS-CoV-2 vaccinations. Fifty-four participants became infected with SARS-CoV-2 during the observation period (median=79 weeks from ART initiation). Study participants who became infected with SARS-CoV-2 after ART had lower volumes at the time of enrollment in several subcortical brain regions with the most pronounced effect in the pallidum (p=.025). There were no associations between brain volumes and ratings of mood, demographics, or HIV disease indices. SARS-CoV-2 infection was two-fold higher among individuals who reported use of amyl nitrites (i.e., poppers) during chemsex. Machine learning with repeated cross validation revealed that lower orbital and medial frontal lobe, anterior cingulate, pallidum, vermis, and olfactory volumes, worse motor function, and higher education collectively predicted co-infection status (average AUC of 85%). Conclusion(s): Study findings point toward a risk phenotype for SARS-CoV-2 infection among PWH defined by pre-existing differences in brain volumes relevant to risk-taking behavior, emotion, and neuroHIV as well as behavioral factors such as inhalant use and lack of social distancing during chemsex. (Table Presented).

Psychosomatic state and laboratory parameters of COVID-19 convalescent patients.

Objective. To evaluate some parameters of the psychosomatic state, cytokine levels (IL-6, IL-8, IL-17A), and free radical status (levels of nitrates and nitrites, antioxidant plasma activity) in convalescent patients after severe COVID-19. Patients and methods. We examined 64 patients who had severe COVID-19 and underwent either a 30-35-day course of inpatient rehabilitation after their discharge from a hospital for infectious diseases or a 60-65-day course of outpatient rehabilitation at the Ambulatory Center of Nalchik, Clinical Hospital No 1. Results. We surveyed patients after severe COVID-19 and found that they required a long rehabilitation. Many of them reported asthenic syndrome, psycho-emotional disorders, and other complaints upon discharge from the hospital. Serum levels of proinflammatory cytokines remained high in patients after severe COVID-19 even 30-35 days following their discharge (p < 0.05). Serum levels of IL-6, IL-8, nitrites, and nitrates remained elevated on days 60-65 following discharge (p < 0.05), despite comprehensive therapy in a rehabilitation department. Plasma antioxidant activity was reduced, whereas IL-17A level normalized by this time. Conclusion. Our findings suggest that currently used rehabilitation measures for COVID-19 are insufficient. Adequate rehabilitation of convalescent COVID-19 patients requires proper monitoring of their immune system condition, as well as new effective methods for immune correction and restoration of their psychoemotional status after the acute phase of the disease.Copyright © 2022, Dynasty Publishing House. All rights reserved.

The role of reactive nitrogen species as biomarkers of disease severity in COVID-19

Reactive nitrogen species (RNS) such as nitric oxide (NO) can be produced by local pulmonary cells and inflammatory cells, and they play a role in the pathogenesis of chronic pulmonary diseases and pulmonary infections. NO is an unstable compound turning to a more stable nitrite and nitrate rapidly. The objective of our study was to investigate the association between plasma nitrate+nitrite, nitrate, and nitrite levels and the severity of coronavirus disease (COVID)-19. Blood plasma samples of mild, moderate, and severe COVID-19 patients were collected from 2 different hospitals. Plasma of healthy subjects, who had never COVID-19 was used as controls (n=20 for each group). Samples were isolated by centrifugation following ultrafiltration prior to the commercial nitrate/nitrite colorimetric assay kit. Plasma nitrate+nitrite and nitrate levels, respectively, were significantly increased in severe patients (medians=34.4muM and 33.4muM), as compared to mild groups (medians=22.3muM and 20.6muM;p<0.05). In contrast, nitrite levels were significantly lower in severe patients (median= 0.8muM) than mild patients (median= 1.6muM;p<0.0001). Patients with severe disease were older (64.9 years) than the mild patients (50.6 years;p<0.05). In severe patients, age was positively correlated with nitrate+nitrite and nitrate levels, respectively (r=0.502, p=0.024;r=0.489, p=0.029). Our findings suggest that RNS may play a role in the pathogenesis of COVID-19 and that it may be considered as a marker of severity.

Serum markers of endothelial dysfunction and invasive mechanical ventilation in COVID-19

Introduction: Sars-Cov-2 infection induces vascular endothelium damage at pulmonary and systemic level. Alterations on immunity response generate inappropriate endothelial activation through pro-inflammatory cytokines release, up-regulated expression of adhesion molecules, leukocyte migration, increased nitric oxide requirements and oxidative stress. Endothelial function is a key feature in the pathogenesis of COVID-19. Objective(s): To evaluate circulating markers associated with endothelial activation in hospitalized patients with COVID-19 and determine the difference between patients who required invasive mechanical ventilation (IMV) and those who did not. Method(s): Cross-sectional study. Subjects with a confirmed diagnosis of COVID-19 and >18 years old were included. Patients who did not require hospitalization were excluded. Serum markers of endothelial function were tested during hospitalization and protein adjustment was performed. Result(s): A total of 390 patients were studied, with an average age of 57+/-13 years old. Patients who required invasive mechanical ventilation had higher prevalence of diabetes (34.53% vs 11.54%;p=0.020), higher serum nitrite levels (0.028 mmol/L [0.094-0.647] vs 0.07 [0.03-0.24];p=0.003), nitrates (0.363mmol/L [0.100- 0.591] vs 0.130[0.003-0.374];p=0.004) and E-selectin (1.00 ng/mg [0.79-1.32] vs 0.84 [0.55-1.09];p=0.019) when compared to non-IMV patients. Higher levels of nitrites adjusted by proteins were associated with an increased risk for IMV (OR 5.59, CI 95 1.15-27.00, p=0.032). Conclusion(s): Patients with increased nitrites and E-selectin levels had worse endothelial dysfunction and a higher risk for IMV during hospitalization.

Renal replacement therapy removes a large number of nitric oxide donors responsible for the nitrate-nitrite-nitric oxide pathway.

BACKGROUNDS: Nitric oxide has a broad-spectrum antibacterial property promising as a new therapeutic agent for severe acute respiratory syndrome coronavirus-2 because nitric oxide donor (such as S-nitroso-N-acetylpenicillamine) reduces the replication of coronavirus-2. Patients with coronavirus disease 2019 undergoing dialysis generally have a higher mortality rate than the general population. Although the higher mortality rate in these patients may be related to their advanced age, it has been suggested that plasma nitrite and nitrate levels (products of nitric oxide metabolism) are significantly decreased after hemodialysis which may compromise the nitrate-nitrite-nitric oxide pathway and impair nitric oxide homeostasis. It results in increased cardiovascular mortality in patients undergoing dialysis. However, the profile of nitric oxide-producing substances is poorly understood during renal replacement therapy. METHODS: We simulated continuous hemodialysis and hemodiafiltration to measure the amount of nitric oxide (nitric oxide-producing substance) clearance in vitro. RESULTS: The results demonstrated increased nitric oxide clearance and higher clearance than creatinine (molecular weight: 113) and vitamin B12 (molecular weight: 1355) using highly efficient renal replacement therapy modes. CONCLUSION: The high nitric oxide clearance may have partly contributed to the high cardiovascular and coronavirus-2 mortality risk in patients on dialysis.

Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of COVID-19: A Revaluation of Pauling's Vitamin C Therapy.

Linus Pauling, who was awarded the Nobel Prize in Chemistry, suggested that a high dose of vitamin C (l-ascorbic acid) might work as a prevention or treatment for the common cold. Vitamin C therapy was tested in clinical trials, but clear evidence was not found at that time. Although Pauling's proposal has been strongly criticized for a long time, vitamin C therapy has continued to be tested as a treatment for a variety of diseases, including coronavirus infectious disease 2019 (COVID-19). The pathogen of COVID-19, SARS-CoV-2, belongs to the ß-coronavirus lineage, which includes human coronavirus, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). This review intends to shed new light on vitamin C antiviral activity that may prevent SARS-CoV-2 infection through the chemical production of nitric oxide (NO). NO is a gaseous free radical that is largely produced by the enzyme NO synthase (NOS) in cells. NO produced by upper epidermal cells contributes to the inactivation of viruses and bacteria contained in air or aerosols. In addition to enzymatic production, NO can be generated by the chemical reduction of inorganic nitrite (NO2-), an alternative mechanism for NO production in living organisms. Dietary vitamin C, largely contained in fruits and vegetables, can reduce the nitrite in saliva to produce NO in the oral cavity when chewing foods. In the stomach, salivary nitrite can also be reduced to NO by vitamin C secreted from the epidermal cells of the stomach. The strong acidic pH of gastric juice facilitates the chemical reduction of salivary nitrite to produce NO. Vitamin C contributes in multiple ways to the host innate immune system as a first-line defense mechanism against pathogens. Highlighting chemical NO production by vitamin C, we suggest that controversies on the therapeutic effects of vitamin C in previous clinical trials may partly be due to less appreciation of the pleiotropic functions of vitamin C as a universal bioreductant.

Nitrite enhanced detection from saliva by simple geometrical modifications of paper-based micromixers.

Dysregulation of nitric oxide (NO) and it's two relatively stable metabolites, nitrite, and nitrate, in SARS-CoV-2, are reported in infected populations, especially for nitrates levels > 68.4 µmol/L. In this paper, we measure the abnormal presence of nitrite in the saliva by developing a cheap µPAD for colorimetric detection through the modified Griess reaction. This includes a diazotization reaction between nitrite and Griess reagent, including Sulfanilamide and N-Naphthyl-ethylenediamine in an acidic medium, causing a pink Azo compound. The modifications are suggested by a numerical method model that couples the mass flux with the porosity medium equations (convection, diffusion and, dispersion) that improves the mixing process. The mixing index was quantified from the concentration deviation method via simulation of a homogeneous two-phase flow in a porous environment. Five µPAD designs were fabricated to verify the simulation results of mixing enhancement on the Griess reactants in saliva samples. The investigated geometries include straight, helical, zig-zag, square wave, and inclined jagged shapes fabricated by direct laser writing, suitable for low cost, mass fabrication. Inclined jagged micromixer exhibited the best performance with up to 40% improvement compared with the simple straight geometry. Deliberate geometrical modifications, exemplified here in a jagged micromixer on paper, cut the limit of detection (LOD) by at least half without impacting the linear detection range.

SLE After SARS-COV-2 Infection

SARS-COV-2 infection is often associated with exaggerated immune response, also referred to as a ‘cytokine storm’. There is growing concern that it may be linked to autoimmunity, with many cases of autoimmune diseases either triggered by or related to SARS-COV-2 having been reported, ranging from Guillain-Barre syndrome, Graves’ disease, multiple sclerosis, Kawasaki-like disease. Our patient was a 20-year-old female with a history of hidradenitis who presented with malaise, feet and ankle swelling, asthenia, anorexia, weight loss of 50 Ibs of 4 months. She had COVID pneumonia 7 months prior and was also seen in the ER thrice afterwards for ankle pain and fatigue managed with antibiotics and analgesics. Exam findings included tender bilateral lower extremity edema, diffuse hyperkeratotic and hyperpigmented purpuric rashes and bilateral suppurative axillary swellings. She was admitted for protein-energy malnutrition. Blood work showed WBC 13.5, low Hb 9.3, AST 509, ALT 104, BUN 29, Creatinine 0.9, Protein 7.5, albumin 1.5 (globulin gap of 6). Urine assay showed 3+ proteinuria Hb 3+ with RBC 3-10/hpf, absent nitrite, LE 1+, protein/creatinine ratio was 2949 mg/g. Blood cultures returned negative. US showed trace pericardial effusion and normal kidneys. Infectious workup returned negative for anti-streptolysin O, HIV, hepatitis B and C. Two days after, she developed AMS, fever, tachycardia and neck stiffness concerning for possible meningoencephalitis. CT head was normal. Lumbar puncture was performed. IV vancomycin and piperacillin-tazobactam was started. CSF fluid analysis revealed total protein of 125mg/dl, elevated IgG 79.8, concerning for an underlying inflammatory pathology. EEG was unremarkable. She became oliguric with creatinine and BUN both peaking at 2.6 and 58 respectively. Renal ultrasound revealed medical renal disease. Urine microscopy showed granular cast and no dysmorphic RBCs. ANA, anti-smith SSA, SSB, DS-DNA, RF, smooth muscle, anti-histone, anti-centromere, JO-1 and RNP antibodies were markedly elevated. She was unstable for CT trocar biopsy of the kidney. She subsequently went into cardiac arrest multiple times about a week into admission, before eventually expiring. Though causation was not established in our patient, SARS-COV-2 infection causing exaggerated immune response may unmask SLE or be associated with SLE.

From Inferior Vena Cava to Right Atrium: A Rare Case of a Unique Large Burden Thrombus in a Patient with Antiphospholipid Syndrome

Introduction: Antiphospholipid Syndrome is a condition where self-antibodies are directed against phospholipid binding proteins resulting in thrombosis and/or pregnancy loss. Diagnosis is made via history, physical, positive anticardiolipin and anti-beta-2-glycoprotein antibodies. We describe a case of a large thrombus in a previously diagnosed patient with antiphospholipid syndrome and discuss the need for prophylaxis in these patients. Case Report: 34-year-old G7P1161 Hispanic female with past medical history of uncontrolled diabetes mellitus type 2 presents with an acute onset of sharp abdominal pain radiating to the back associated with nausea, non-bloody non-bilious emesis and dysuria. Vital signs on admission are significant for tachycardia and hypertension. Labs are noteworthy for elevated Creatinine at 1.7 mg/dl, thrombocytopenia, transaminitis, elevated Ddimer at 14272 ng/ml. Urine analysis is positive for nitrites, trace leukocytes and bacteria. Her serum pregnancy test and COVID PCR are negative. CT Abdomen/Pelvis with contrast revealed an extensive thrombus in the Inferior Vena Cava (IVC) to the Right Atrium (RA), also extending into the hepatic veins and upper lumbar veins. Moderate perinephric fat stranding is also noted around bilateral kidneys. Ultrasound of the abdomen reveals cholelithiasis without evidence of acute cholecystitis. Venous Doppler of lower extremities reveals patent deep veins. Patient was started on heparin drip immediately and intravenous Cefepime. Interventional Radiology performed mechanical thrombectomy. Hematology was consulted and converted patient to Warfarin with an INR goal of 2.5-3. Patient was discharged and instructed to follow up with hematology. Discussion: There are few case reports of extensive thrombi ranging from IVC to RA with most cases occurring in elderly population. We present a unique case of an extensive thrombus ranging not only from the IVC to RA but also extending into the hepatic veins and the upper lumbar veins. The patient described has a history of multiple spontaneous abortions with her only successful preterm birth required daily therapeutic Lovenox during pregnancy. Her recurrent pregnancy loss and current large burden thrombus can be attributed to her antiphospholipid syndrome. This begs the question whether these patients should be started on prophylaxis anticoagulation. There have been limited studies with aspirin and warfarin which at times demonstrated positive results. Our patient had her thrombus identified incidentally due to an admission for pyelonephritis. If her thrombus was not recognized in time, outcomes could have been devastating. In conclusion, there should be further studies to determine the efficacy of anticoagulation prophylaxis in patients with positive antiphospholipid antibodies. (Figure Presented).

On the origin of nitrosylated hemoglobin in COVID-19: Endothelial NO capture or redox conversion of nitrite?: Experimental results and a cautionary note on challenges in translational research.

In blood, the majority of endothelial nitric oxide (NO) is scavenged by oxyhemoglobin, forming nitrate while a small part reacts with dissolved oxygen to nitrite; another fraction may bind to deoxyhemoglobin to generate nitrosylhemoglobin (HbNO) and/or react with a free cysteine to form a nitrosothiol. Circulating nitrite concentrations in healthy individuals are 200-700 nM, and can be even lower in patients with endothelial dysfunction. Those levels are similar to HbNO concentrations ([HbNO]) recently reported, whereby EPR-derived erythrocytic [HbNO] was lower in COVID-19 patients compared to uninfected subjects with similar cardiovascular risk load. We caution the values reported may not reflect true (patho)physiological concentrations but rather originate from complex chemical interactions of endogenous nitrite with hemoglobin and ascorbate/N-acetylcysteine. Using an orthogonal detection method, we find baseline [HbNO] to be in the single-digit nanomolar range; moreover, we find that these antioxidants, added to blood collection tubes to prevent degradation, artificially generate HbNO. Since circulating nitrite also varies with lifestyle, dietary habit and oral bacterial flora, [HbNO] may not reflect endothelial activity alone. Thus, its use as early marker of NO-dependent endothelial dysfunction to stratify COVID-19 patient risk may be premature. Moreover, oxidative stress not only impairs NO formation/bioavailability, but also shifts the chemical landscape into which NO is released, affecting its downstream metabolism. This compromises the endothelium's role as gatekeeper of tissue nutrient supply and modulator of blood cell function, challenging the body's ability to maintain redox balance. Further studies are warranted to clarify whether the nature of vascular dysfunction in COVID-19 is solely of endothelial nature or also includes altered erythrocyte function.

Serum nitrite and nitrate: A potential biomarker for post-covid-19 complications?

Nitric oxide (NO) plays an important role in cardiovascular and immune systems. Quantification of blood nitrite and nitrate, two relatively stable metabolites of NO (generally as NOx), has been acknowledged, in part, representing NO bioactivity. Dysregulation of NOx had been reported in SARS-CoV-2 infected populations, but whether patients recovered from COVID-19 disease present with restored NOx is unknown. In this study, serum NO2- and NO3- were quantified and analyzed among 109 recovered adults in comparison to a control group of 166 uninfected adults. Nitrite or nitrate levels were not significantly different among mild-, common-, severe- and critical-type patients. However, these recovered patients had dramatically lower NO2- and NO2-/NO3- than the uninfected group (p < 0.0001), with significantly higher NO3- levels (p = 0.0023) than the uninfected group. Nitrate and nitrite/nitrate were positively and negatively correlated with patient age, respectively, with age 65 being a turning point among recovered patients. These results indicate that low NO2-, low NO2-/NO3- and high NO3- may be potential biomarkers of long-term poor or irreversible outcomes after SARS-CoV-2 infection. It suggests that NO metabolites might serve as a predictor to track the health status of recovered COVID-19 patients, highlighting the need to elucidate the role of NO after SARS-CoV-2 infection.

Future antiviral polymers by plasma processing.

Coronavirus disease 2019 (COVID-19) is largely threatening global public health, social stability, and economy. Efforts of the scientific community are turning to this global crisis and should present future preventative measures. With recent trends in polymer science that use plasma to activate and enhance the functionalities of polymer surfaces by surface etching, surface grafting, coating and activation combined with recent advances in understanding polymer-virus interactions at the nanoscale, it is promising to employ advanced plasma processing for smart antiviral applications. This trend article highlights the innovative and emerging directions and approaches in plasma-based surface engineering to create antiviral polymers. After introducing the unique features of plasma processing of polymers, novel plasma strategies that can be applied to engineer polymers with antiviral properties are presented and critically evaluated. The challenges and future perspectives of exploiting the unique plasma-specific effects to engineer smart polymers with virus-capture, virus-detection, virus-repelling, and/or virus-inactivation functionalities for biomedical applications are analysed and discussed.

Effects of nitrite and far-red light on coagulation.

Nitric oxide, NO, has been explored as a therapeutic agent to treat thrombosis. In particular, NO has potential in treating mechanical device-associated thrombosis due to its ability to reduce platelet activation and due to the central role of platelet activation and adhesion in device thrombosis. Nitrite is a unique NO donor that reduces platelet activation in that it's activity requires the presence of red blood cells whereas NO activity of other NO donors is blunted by red blood cells. Interestingly, we have previously shown that red blood cell mediated inhibition of platelet activation by adenosine diphosophate (ADP) is dramatically enhanced by illumination with far-red light that is likely due to photolysis of red cell surface bound NO congeners. We now report the effects of nitrite, far-red light, and their combination on several measure of blood coagulation using a variety of agonists. We employed turbidity assays in platelet rich plasma, platelet activation using flow cytometry analysis of a fluorescently labeled antibody to the activated platelet fibrinogen binding site, multiplate impedance-based platelet aggregometry, and assessment of platelet adhesion to collagen coated flow-through microslides. In all cases, the combination of far-red light and nitrite treatment decreased measures of coagulation, but in some cases mono-treatment with nitrite or light alone had no effect. Perhaps most relevant to device thrombosis, we observed that platelet adhesions was inhibited by the combination of nitrite and light treatment while nitrite alone and far-red light alone trended to decrease adhesion, but the results were mixed. These results support the potential of combined far-red light and nitrite treatment for preventing thrombosis in extra-corporeal or shallow-tissue depth devices where the far-red light can penetrate. Such a combined treatment could be advantageous due to the localized treatment afforded by far-red light illumination with minimal systemic effects. Given the role of thrombosis in COVID 19, application to treatment of patients infected with SARS Cov-2 might also be considered.

Blood nitrate and nitrite modulating nitric oxide bioavailability: Potential therapeutic functions in COVID-19.

Most outcomes of COVID-19 are associated with dysfunction of the vascular system, particularly in the lung. Inhalation of nitric oxide (NO) gas is currently being investigated as a treatment for patients with moderate to severe COVID-19. In addition to the expected vasodilation effect, it has been also suggested that NO potentially prevents infection by SARS-CoV-2. Since NO is an unstable radical molecule that is easily oxidized by multiple mechanisms in the human body, it is practically difficult to control its concentration at lesions that need NO. Inorganic nitrate and/or nitrite are known as precursors of NO that can be produced through chemical as well enzymatic reduction. It appears that this NO synthase (NOS)-independent mechanism has been overlooked in the current developing of clinical treatments. Here, I suggest the missing link between nitrate and COVID-19 in terms of hypoxic NO generation.