[ACTIV SARS-CoV-2 registry (Analysis of Chronic Non-infectious Diseases Dynamics After COVID-19 Infection in Adult Patients). Assessment of impact of combined original comorbid diseases in patients with COVID-19 on the prognosis].

AIM: Study the impact of various combinations of comorbid original diseases in patients infected with COVID-19 later on the disease progression and outcomes of the new coronavirus infection. MATERIALS AND METHODS: The ACTIV registry was created on the Eurasian Association of Therapists initiative. 5,808 patients have been included in the registry: men and women with COVID-19 treated at hospital or at home. CLINICALTRIALS: gov ID NCT04492384. RESULTS: Most patients with COVID-19 have original comorbid diseases (oCDs). Polymorbidity assessed by way of simple counting of oCDs is an independent factor in negative outcomes of COVID-19. Search for most frequent combinations of 2, 3 and 4 oCDs has revealed absolute domination of cardiovascular diseases (all possible variants). The most unfavorable combination of 2 oCDs includes atrial hypertension (AH) and chronic heart failure (CHF). The most unfavorable combination of 3 oCDs includes AH, coronary heart disease (CHD) and CHF; the worst combination of 4 oCDs includes AH, CHD, CHF and diabetes mellitus. Such combinations increased the risk of lethal outcomes 3.963, 4.082 and 4.215 times respectively. CONCLUSION: Polymorbidity determined by way of simple counting of diseases may be estimated as a factor in the lethal outcome risk in the acute phase of COVID-19 in real practice. Most frequent combinations of 2, 3 and 4 diseases in patients with COVID-19 primarily include cardiovascular diseases (AH, CHD and CHF), diabetes mellitus and obesity. Combinations of such diseases increase the COVID-19 lethal outcome risk.

Analysis of influence of background therapy for comorbidities in the period before infection on the risk of the lethal COVID outcome. Data from the international ACTIV SARS-CoV-2 registry («Analysis of chronic non-infectious diseases dynamics after COVID-19 infection in adult patients SARS-CoV-2¼).

Aim      To study the effect of regular drug therapy for cardiovascular and other diseases preceding the COVID-19 infection on severity and outcome of COVID-19 based on data of the ACTIVE (Analysis of dynamics of Comorbidities in paTIents who surVived SARS-CoV-2 infEction) registry.Material and methods  The ACTIVE registry was created at the initiative of the Eurasian Association of Therapists. The registry includes 5 808 male and female patients diagnosed with COVID-19 treated in a hospital or at home with a due protection of patients' privacy (data of nasal and throat smears; antibody titer; typical CT imaging features). The register territory included 7 countries: the Russian Federation, the Republic of Armenia, the Republic of Belarus, the Republic of Kazakhstan, the Kyrgyz Republic, the Republic of Moldova, and the Republic of Uzbekistan. The registry design: a closed, multicenter registry with two nonoverlapping arms (outpatient arm and in-patient arm). The registry scheduled 6 visits, 3 in-person visits during the acute period and 3 virtual visits (telephone calls) at 3, 6, and 12 mos. Patient enrollment started on June 29, 2020 and was completed on October 29, 2020. The registry completion is scheduled for October 29, 2022. The registry ID: ClinicalTrials.gov: NCT04492384. In this fragment of the study of registry data, the work group analyzed the effect of therapy for comorbidities at baseline on severity and outcomes of the novel coronavirus infection. The study population included only the patients who took their medicines on a regular basis while the comparison population consisted of noncompliant patients (irregular drug intake or not taking drugs at all despite indications for the treatment).Results The analysis of the ACTIVE registry database included 5808 patients. The vast majority of patients with COVID-19 had comorbidities with prevalence of cardiovascular diseases. Medicines used for the treatment of COVID-19 comorbidities influenced the course of the infectious disease in different ways. A lower risk of fatal outcome was associated with the statin treatment in patients with ischemic heart disease (IHD); with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor antagonists and with beta-blockers in patients with IHD, arterial hypertension, chronic heart failure (CHF), and atrial fibrillation; with oral anticoagulants (OAC), primarily direct OAC, clopidogrel/prasugrel/ticagrelor in patients with IHD; with oral antihyperglycemic therapy in patients with type 2 diabetes mellitus (DM); and with long-acting insulins in patients with type 1 DM. A higher risk of fatal outcome was associated with the spironolactone treatment in patients with CHF and with inhaled corticosteroids (iCS) in patients with chronic obstructive pulmonary disease (COPD).Conclusion      In the epoch of COVID-19 pandemic, a lower risk of severe course of the coronavirus infection was observed for patients with chronic noninfectious comorbidities highly compliant with the base treatment of the comorbidity.

[International register "Analysis of Chronic Non-infectious Diseases Dynamics After COVID-19 Infection in Adult Patients (ACTIV SARS-CoV-2)"].

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Influence of hydrometeorological indices on electrolytes and trace elements homeostasis in patients with ischemic heart disease.

One hundred patients with ischemic heart disease and 70 healthy subjects were on unified regimen. Urine was collected with 4-h proportions during 3-5 days (72-120 h). Each portion of urine was analyzed for macro- (Na, K, P, Cl, Ca, Mg) and microelements (Fe, Cu, Zn, Cr, Cd, V). Temporal structure (biological and hydrometeorological indices) parameters have been estimated by nonlinear least squares method for sinusoidal rhythms and dispersion analysis for nonsinusoidal rhythms. Data of weather indices were received from the hydrometeorological service of the Republic of Armenia in 2015 at 3-h intervals. Statistically significant rhythms were observed in healthy subjects in 91% cases of 593 rhythmological investigations of water-mineral homeostasis. Acrophases of water-mineral homeostasis mostly had individual nature. Healthy subjects' rhythms of water-mineral excretion were depending on rhythms of hydrometeorological indices and were characterized with significant correlative connections. Acrophases of indices of water-mineral homeostasis mostly were outstripping the acrophases of the rhythms of hydrometeorological indices. Chronostructure of water-mineral homeostasis in patients with ischemic heart disease was characterized with infradian and circadian fluctuations. In case of individuals with ischemic heart disease, statistically significant correlative connections between rhythms of water-mineral excretion and rhythms of hydrometeorological indices differ in comparison with the results of practically healthy individuals. In patients with ischemic heart disease, acrophases of biorhythms often were concurrent or delayed relative to the acrophases of the rhythms of hydrometeorological indices.

[The impact of BMI on the course of the acute SARS-COV-2 infection and the risks that emerge during the first year after the hospital discharge. Subanalysis evidence of the AKTIV and AKTIV 2 registries].

BACKGROUND: There is enough evidence of the negative impact of excess weight on the formation and progression of res piratory pathology. Given the continuing SARS-CoV-2 pandemic, it is relevant to determine the relationship between body mass index (BMI) and the clinical features of the novel coronavirus infection (NCI). AIM: To study the effect of BMI on the course of the acute SARS-COV-2 infection and the post-covid period. MATERIALS AND METHODS: AKTIV and AKTIV 2 are multicenter non-interventional real-world registers. The АКТИВ registry (n=6396) includes non-overlapping outpatient and inpatient arms with 6 visits in each. The АКТИВ 2 registry (n=2968) collected  the  data  of  hospitalized  patients  and  included  3  visits.  All  subjects  were  divided  into  3  groups:  not  overweight  (n=2139), overweight (n=2931) and obese (n=2666). RESULTS: A higher BMI was significantly associated with a more severe course of the infection in the form of acute kidney injury (p=0.018), cytokine storm (p<0.001), serum C-reactive protein over 100 mg/l (p<0.001), and the need for targeted therapy (p<0.001) in the hospitalized patients. Obesity increased the odds of myocarditis by 1,84 times (95% confidence interval [CI]: 1,13-3,00) and the need for anticytokine therapy by 1,7 times (95% CI: 1,30-2,30).The  patients  with  the  1st  and  2nd  degree  obesity,  undergoing  the  inpatient  treatment,  tended  to  have  a  higher  probability  of  a  mortality  rate.  While  in  case  of  morbid  obesity  patients  this  tendency  is  the  most  significant  (odds  ratio  -  1,78; 95% CI: 1,13-2,70). At the same time, the patients whose chronical diseases first appeared after the convalescence period, and those who had certain complaints missing before SARS-CoV-2 infection, more often had BMI of more than 30 kg/m2 (p<0,001).Additionally, the odds of death increased by 2,23 times (95% CI: 1,05-4,72) within 3 months after recovery in obese people over the age of 60 yearsCONCLUSION.  Overweight  and/or  obesity  is  a  significant  risk  factor  for severe  course  of  the  new  coronavirus  infection  and  the associated cardiovascular and kidney damage Overweight people and patients with the 1st and 2nd degree obesity tend to have a high risk of death of SARS-CoV-2 infection in both acute and post-covid periods. On top of that, in case of morbid obesity patients this tendency is statistically significant. Normalization of body weight is a strategic objective of modern medicine and can contribute to prevention of respiratory conditions, severe course and complications of the new coronavirus infection.

Nitric oxide - an activating factor of adenosine deaminase 2 in vitro.

In this study we have investigated the effect of reactive oxygen species produced by some chemicals in aqueous solutions on activity of adenosine deaminase 2 (ADA2) purified from human blood plasma. An activating effect on ADA2 was observed in vitro with sodium nitroprusside (SNP), the source of NO (nitrosonium ions NO(-) in aqueous solutions). Not SH-groups of cysteine but other amino acid residues sensitive to NO were responsible for ADA2 activation. The SNP-derived activation was more pronounced when purified ADA2 was preincubated with heparin and different proteins as an experimental model of the protein environment in vivo. The most effective was heparin, which is known for its ability to regulate enzyme and protein functions in extracellular matrix. We conclude that ADA2 is a protein with flexible conformation that is affected by the protein environment, and it changes its activity under oxidative (nitrosative) stress.

PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: role of PYPAF1 in inflammation.

OBJECTIVE: To gain insight into the pathophysiology of an unusual autoinflammatory syndrome, in a patient of Armenian origin, that mimicked familial Mediterranean fever (FMF) but with episodes triggered by generalized exposure to cold, and to further elucidate the controversial function of the protein encoded by PYPAF1, whose mutations (exclusively missense to date) have been identified in 3 hereditary recurrent fever syndromes. METHODS: The patient's DNA was screened for mutations in both MEFV, the gene responsible for FMF, and PYPAF1. The ability of different recombinant PYPAF1 isoforms, expressed in HEK 293 cells, to regulate NF-kappaB signaling was subsequently assessed. RESULTS: No disease-causing mutation was found in MEFV. However, a nonsense mutation (p.Arg554X) was identified in PYPAF1; this defect resulted in a truncated protein lacking all leucine-rich repeats. Study of the wild-type and mutant PYPAF1 recombinant proteins revealed that PYPAF1 inhibited NF-kappaB proinflammatory pathways, and that the identified nonsense mutation impaired this property. CONCLUSION: These molecular and clinical findings, together with the clinical manifestations in the patient, which call into question the current nosology of the hereditary recurrent fever syndromes, are consistent with the hypothesis that PYPAF1 acts as an inhibitor of NF-kappaB signaling. They also provide a clear elucidation of the functional consequences of this nonsense PYPAF1 mutation not previously described in the literature, which result in a partial loss of function and may thereby explain the pathophysiology of the autoinflammatory syndrome observed in this patient.

Activity of enzymes of adenyline compounds metabolism during crush and decompression of muscle tissue. Part I. Adenylate deaminase activity at experimental crush syndrome.

INTRODUCTION: The number of works on investigation of crush syndrome (CS) pathogenesis, of organs and enzymatic systems at traumatic toxicosis is rather limited. While the clinical current of trauma and the lethality prognosis depend on a degree of violations in them. Such investigations are necessary for opportune diagnosis and definition of a treatment tactic. To complete this deficiency, adenylate deaminase (AMPD) level was studied in twelve tissues at experimental CS in vivo. RESULTS: The experimental model of CS on white rats was caused by crush and decompression of femoral muscle tissue. The CS influence on AMPD activity was investigated in hemisphere, cerebellum, hypothalamus, pituitary body, heart, lung, liver, spleen, kidney, adrenal, crushed and not crushed muscles. In muscles, kidney, pituitary body and adrenal the activity decreased in 2 hours crush but the compensation of effect is observed after 5 hours crush. In cerebellum, hemisphere, heart, liver and lung it decreased during both of crush times. After 2 and 5 hours crush in hypothalamus and in spleen AMPD activity appeared much higher than in control. After 2 hours crush at the end of 48 hours decompression, the activity in muscles, kidney, adrenal and pituitary body was lower, in cerebellum, hypothalamus, hemisphere and heart--higher than, in lung, spleen and liver--close to control. After 5 hours crush in the majority of studied tissues at the end of decompression, the activity was below of control. The greatest deviance was observed in muscles. As to brain in cerebellum and hemisphere the parameter was close to, in pituitary body and in hypothalamus it was 1,5-fold of control. CONCLUSION: AMPD level in the most of studied tissues differs from the control at definite time of crush and decompression. These results mean the possibility of nucleotides pool balance distortion and intermediates accumulation.

Activity of enzymes of adenyline compounds metabolism during crush and decompression of muscle tissue. Part II. Adenosine deaminase activity at experimental crush syndrome.

INTRODUCTION: Publications on investigation of crush syndrome pathogenesis, particularly of enzymatic systems upon traumatic toxicosis are rather limited. Such investigations are necessary for opportune diagnosis and definition of a treatment tactic. To replenish this deficiency, the adenosine deaminase level was studied in 12 rat tissues at experimental crush syndrome in vivo. RESULTS: The experimental model of crush syndrome on white rats was induced by crush and decompression of femoral muscle tissue. The crush syndrome influence on activity of adenosine deaminase isoenzymes was investigated in hemisphere, cerebellum, hypothalamus, pituitary body, heart, lung, liver, spleen, kidney, adrenal, as well as in crushed and native muscles. In 2 and 5 hours after compression, the enzyme activity decreased in muscles, lung and heart; increased in hypothalamus; remains near the control value in kidney and spleen. In cerebellum the parameter practically does not vary during 2 hours compression, while increased in 5 hours. In adrenal, liver, pituitary body and hemisphere the data after 5 hours compression approximated the level of control value in account of compensating mechanism. In 48 hours decompression after 2 hours crush, the adenosine deaminase activity becomes higher than control value in hemisphere, hypothalamus, cerebellum, liver, heart, adrenal, intact muscle, lung and kidney; in the crushed muscle and spleen the activity is reduced down to 60% of control value. In 48 hours decompression after 5 hours compression, the enzyme activity is higher than control value in hypothalamus, pituitary body, hemisphere, cerebellum, kidney, adrenal, heart and lung. The activity is reduced in muscles, spleen and liver. CONCLUSION: The level of adenosine deaminase in most of studied tissues differs from the control value depending on compression and decompression time. It is worthy of note that namely during decompression, the enzyme level deviates from the control in the majority of tissues.