Comparison of REMS, NEWS, qSOFA and SIRS criteria scales for sepsis prediction in patients with diagnosis “SARS-CoV-2, virus unidentified”: a retrospective observational study

Background. Despite ample research on the coronavirus infection sequence and therapy, the incidence of adverse outcomes remains very high. Sepsis stands among the major factors greatly complicating treatment and increasing the risk of death. A timely identification of highrisk sepsis patients is a cornerstone of effective sepsis prevention.Objectives. A comparative prognostic power assessment between the quick Sequential Organ Failure Assessment (qSOFA) scale, National Early Warning Score (NEWS), Initial Prehospital Rapid Emergency Medicine Score (REMS) and the Systemic Inflammatory Response Syndrome (SIRS) criteria for sepsis detection in anaesthetic intensive care patients with a diagnosis: SARS-CoV-2, virus unidentified.Methods. A retrospective observational study included 166 patients over 18-year age with unconfirmed infection (ICD-10 code U07.2). The qSOFA, NEWS, REMS and SIRS point estimates were obtained from each patient. The patients were retrospectively divided in two cohorts by sepsis presence (Sepsis-3 criteria) to determine the express scales power in evaluating the risk of sepsis (estimated as area under ROC curve, AUROC).Results. Data on 102 patients were included in the final analysis. Fifty-eight (57%) patients were terminal, and 55 (54%) developed sepsis. The estimates are as follows: NEWS — AUROC 0.848 [95% confidence interval (CI) 0.764–0.912], sensitivity 76.36% [95% CI 63.0–86.8], specificity 82.98% [95% CI 69.2–92.4], optimal cut-off threshold >5 points; qSOFA — AUROC 0.700 [95% CI 0.602–0.787], sensitivity 76.36% [95% CI 63.0–86.8], specificity 61.70% [95% CI 46.4–75.5], optimal cut-off threshold >0 points; REMS — AUROC 0.739 [95% CI 0.643–0.821], sensitivity 69.09% [95% CI 55.2–80.9], specificity 65.96% [95% CI 50.7–79.1], optimal cut-off threshold >5 points; SIRS criteria — AUROC 0.723 [95% CI 0.626–0.807], sensitivity 98.18% [95% CI 90.3–100.0], specificity 31.91% [95% CI 19.1–47.1], optimal cut-off threshold >0 points.Conclusion. The NEWS scale revealed a good prognostic power to estimate the risk of sepsis in patients with suspected COVID-19 disease. The qSOFA, REMS scales and SIRS criteria possess a good calibration capacity, albeit insufficient resolution, which limits their prognostic value

Clinical and epidemiological characteristics and effectiveness of antiviral therapy for COVID-19 in children: The experience of the first year of the pandemic

Background. The use of antiviral agents can shorten the duration of the viral infection. The aim: to study the clinical and epidemiological features and the effectiveness of antiviral therapy for new coronavirus infection (COVID-19) in outpatient children.Materials and methods. From April 2020 to March 2021, 9334 outpatient children aged from 0 months to 17 years were randomly tested for new coronavirus infection. SARS-CoV-2 RNA was detected in oropharyngeal and nasal material by PCR. Patients with confirmed new coronavirus infection were prescribed interferon-alpha (IFN-α) intranasally, antiviral agents of systemic action. The control group consisted of children with COVID-19 who did not receive treatment.Results. When examining clinically healthy contact children, SARS-CoV-2 RNA was detected in 7.4 % of cases. In the structure of ARI, the specific weight of COVID-19 was 12.3 % with the peak incidence in April-May (up to 22.8 %) and NovemberDecember (up to 30.0 %). In half of the cases, children became infected in the family, and usually adults were the index patient. In 47.7 % of cases, an asymptomatic form of COVID-19 was registered without significant differences in patients of different ages. In one third of children with concomitant pathology, the disease was asymptomatic, in half it was mild, in other cases moderate severity was diagnosed. The clinical picture of COVID-19 did not differ from other ARIs. Anosmia (9.4 %) in half of the cases was combined with ageusia (4.4 %) and was significantly more common in boys. The duration of clinical manifestations in children of the control group and those who received antiviral therapy did not statistically significantly differ in mild and severity of the disease. Also, various antiviral therapy options did not significantly affect the duration of SARS-CoV-2 detection in children with various forms of COVID-19.Conclusion. In the first year of the pandemic, the novel coronavirus infection did not dominate the pattern of respiratory diseases in outpatient children. Further research is required to develop pediatric guidelines for the treatment of COVID-19 at the outpatient stage

Structure of the first representative of Pfam family PF04016 (DUF364) reveals enolase and Rossmann-like folds that combine to form a unique active site with a possible role in heavy-metal chelation.

The crystal structure of Dhaf4260 from Desulfitobacterium hafniense DCB-2 was determined by single-wavelength anomalous diffraction (SAD) to a resolution of 2.01 Å using the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). This protein structure is the first representative of the PF04016 (DUF364) Pfam family and reveals a novel combination of two well known domains (an enolase N-terminal-like fold followed by a Rossmann-like domain). Structural and bioinformatic analyses reveal partial similarities to Rossmann-like methyltransferases, with residues from the enolase-like fold combining to form a unique active site that is likely to be involved in the condensation or hydrolysis of molecules implicated in the synthesis of flavins, pterins or other siderophores. The genome context of Dhaf4260 and homologs additionally supports a role in heavy-metal chelation

Structure of a putative NTP pyrophosphohydrolase: YP_001813558.1 from Exiguobacterium sibiricum 255-15.

The crystal structure of a putative NTPase, YP_001813558.1 from Exiguobacterium sibiricum 255-15 (PF09934, DUF2166) was determined to 1.78 Å resolution. YP_001813558.1 and its homologs (dimeric dUTPases, MazG proteins and HisE-encoded phosphoribosyl ATP pyrophosphohydrolases) form a superfamily of all-α-helical NTP pyrophosphatases. In dimeric dUTPase-like proteins, a central four-helix bundle forms the active site. However, in YP_001813558.1, an unexpected intertwined swapping of two of the helices that compose the conserved helix bundle results in a `linked dimer' that has not previously been observed for this family. Interestingly, despite this novel mode of dimerization, the metal-binding site for divalent cations, such as magnesium, that are essential for NTPase activity is still conserved. Furthermore, the active-site residues that are involved in sugar binding of the NTPs are also conserved when compared with other α-helical NTPases, but those that recognize the nucleotide bases are not conserved, suggesting a different substrate specificity

Structure of the γ-D-glutamyl-L-diamino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-γ-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases.

Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific γ-D-glutamyl-L-diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (L-Ala-γ-D-Glu) enabled the identification of conserved sequence and structural signatures for recognition of L-Ala and γ-D-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial L-alanine-γ-D-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site

The structure of BVU2987 from Bacteroides vulgatus reveals a superfamily of bacterial periplasmic proteins with possible inhibitory function.

Proteins that contain the DUF2874 domain constitute a new Pfam family PF11396. Members of this family have predominantly been identified in microbes found in the human gut and oral cavity. The crystal structure of one member of this family, BVU2987 from Bacteroides vulgatus, has been determined, revealing a β-lactamase inhibitor protein-like structure with a tandem repeat of domains. Sequence analysis and structural comparisons reveal that BVU2987 and other DUF2874 proteins are related to β-lactamase inhibitor protein, PepSY and SmpA_OmlA proteins and hence are likely to function as inhibitory proteins

cisRED: a database system for genome-scale computational discovery of regulatory elements

We describe cisRED, a database for conserved regulatory elements that are identified and ranked by a genome-scale computational system (). The database and high-throughput predictive pipeline are designed to address diverse target genomes in the context of rapidly evolving data resources and tools. Motifs are predicted in promoter regions using multiple discovery methods applied to sequence sets that include corresponding sequence regions from vertebrates. We estimate motif significance by applying discovery and post-processing methods to randomized sequence sets that are adaptively derived from target sequence sets, retain motifs with p-values below a threshold and identify groups of similar motifs and co-occurring motif patterns. The database offers information on atomic motifs, motif groups and patterns. It is web-accessible, and can be queried directly, downloaded or installed locally

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 μM), consistent with docking results. Dihydroacridines inhibited Aβ42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood–brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations. Copyright © 2023 Makhaeva, Kovaleva, Rudakova, Boltneva, Lushchekina, Astakhova, Timokhina, Serebryakova, Shchepochkin, Averkov, Utepova, Demina, Radchenko, Palyulin, Fisenko, Bachurin, Chupakhin, Charushin and Richardson.122041400110-4; FFSN-2021-0005; Alternatives Research and Development Foundation, ARDF; University of Michigan, U-M; Russian Foundation for Basic Research, РФФИ: 19-29-08037; Russian Science Foundation, RSFThis research was partly supported by grant # 22-13-00298 of the Russian Science Foundation and IPAC RAS State Targets Project # FFSN-2021-0005; quantum-chemical calculations were supported the IBCP RAS State Targets Project # 122041400110-4. The synthesis of the compounds was financially supported by the Russian Foundation for Basic Research (research project # 19-29-08037). Support for RR’s contributions to the computer modeling components of the work was provided in part by a grant from the Alternatives Research and Development Foundation (ARDF) and an Mcubed grant from the University of Michigan

Myocardial infarction in the population of some Russian regions and its prognostic value

Aim. To study the prevalence of myocardial infarction (MI) in the population of Russian regions and its contribution to cardiovascular events.Material and methods. The analysis material was representative samples of the population aged 35-64 years from 11 Russian regions,  examined within the multicenter study “Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions  of Russian Federation”. The response rate was about 80%. The study used a community-based  systematic stratified multiply random sample. During the study, information on prior MI was obtained using a standard questionnaire. Anthropometry and measurement of blood pressure (BP) and heart rate (HR) with an automatic BP monitor were performed. Resting electrocardiography (ECG) was performed, followed by Minnesota coding. Major and minor QQS waves and STT segments were considered as ischemic  ECG abnormalities. Biochemical parameters were determined using an Arkhitect 000 Clinical Chemistry Analyzer. The median prospective  follow-up was 6,21 [5,25; 6,75] years. A composite endpoint (CE) was analyzed, including cardiovascular death and non-fatal MI. During the follow-up period, 363 all-cause deaths were detected,  of which 134 were from cardiovascular diseases, while 196 — CEs. Statistical analysis was carried out in R 3.6.1 environment.Results. The MI prevalence among the Russian population was 2,9%; 5,2% for men and 1,5% for women,  increasing  with age. Men with prior MI were  more likely to take statins and beta-blockers  than women as follows: 39,0% vs 25,6% and 29,3% vs 27,1%, respectively. MI newly diagnosed within the follow-up  period was associated with the following risk factors (RFs): smoking, increased BP, HR, triglycerides and glucose.  For individuals with prior MI, a significant relationship was found only with smoking.  Multiple comparison  of the contribution of RFs, ECG abnormalities,  and prior MI showed  that the inclusion of ischemic ECG abnormalities in the analysis significantly increases  the risk of cardiovascular events in individuals without prior MI compared with individuals without both MI and ECG changes.  A high CE risk was noted in patients with prior MI: relative risk (RR), 4,73 (2,92-7,65); the addition of ischemic ECG abnormalities increased the RR to 5,75 (3,76-8,8).Conclusion. The RR of CEs in patients  with prior MI without or with ischemic ECG changes  is 4,73 and 5,75 times higher than in patients without MI and ECG abnormalities. The risk factors  identified  in this case cannot explain such an increase  in CEs. It is obvious  that people  with prior MI need  rehabilitation. The presence of RFs in patients with newly diagnosed  MI indicates insufficient primary prevention, which suggests  that strengthening preventive measures to eliminate conventional risk factors in patients with newly diagnosed  MI will help reduce the risk of recurrent MI or cardiovascular  mortality

Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident

BACKGROUND: Previous studies showed an increased risk of thyroid cancer among children and adolescents exposed to radioactive iodines released after the Chornobyl (Chernobyl) accident, but the effects of screening, iodine deficiency, age at exposure and other factors on the dose-response are poorly understood. METHODS: We screened 11 970 individuals in Belarus aged 18 years or younger at the time of the accident who had estimated (131)I thyroid doses based on individual thyroid activity measurements and dosimetric data from questionnaires. The excess odds ratio per gray (EOR/Gy) was modelled using linear and linear-exponential functions. RESULTS: For thyroid doses \u3c5 \u3eGy, the dose-response was linear (n=85; EOR/Gy=2.15, 95% confidence interval: 0.81-5.47), but at higher doses the excess risk fell. The EOR/Gy was significantly increased among those with prior or screening-detected diffuse goiter, and larger for men than women, and for persons exposed before age 5 than those exposed between 5 and 18 years, although not statistically significant. A somewhat higher EOR/Gy was estimated for validated pre-screening cases. CONCLUSION: 10-15 years after the Chornobyl accident, thyroid cancer risk was significantly increased among individuals exposed to fallout as children or adolescents, but the risk appeared to be lower than in other Chornobyl studies and studies of childhood external irradiation