Применение циклоспорина А у пациентов с COVID-19 при неэффективности первичной иммуносупрессии: ретроспективное когортное псевдорандомизированное исследование

АКТУАЛЬНОСТЬ: Терапия пациентов с новой коронавирусной инфекцией (COronaVIrus Disease 2019 — COVID-19) при прогрессирующем поражении легких на фоне применения глюкокортикостероидов (ГКС) и ингибиторов интерлейкина-6 (ИИЛ-6) до сих пор не разработана. ЦЕЛЬ ИССЛЕДОВАНИЯ: оценка эффективности циклоспорина А у пациентов с COVID-19 при прогрессировании поражения легких и гипоксемической острой дыхательной недостаточностью, получивших патогенетическую терапию ГКС и ИИЛ-6. МАТЕРИАЛЫ И МЕТОДЫ: Ретроспективное когортное псевдорандомизированное моноцентровое исследование (n = 98). Циклоспорин А назначали в первые 72–96 ч после введения ИИЛ-6 при ухудшении состояния пациентов. Пациенты группы сравнения соответствовали основной группе, но не получали терапию циклоспорином А. Первичная конечная точка — госпитальная летальность. Вторичные конечные точки — длительность госпитализации, количество пациентов, поступивших в отделение реанимации и интенсивной терапии (ОРИТ), потребность в респираторной поддержке. РЕЗУЛЬТАТЫ: Летальность составила 12 (22) % в группе циклоспорина и 27 (61) % в группе сравнения, р = 0,001 (относительный риск (ОР) 2,00 [1,12–3,48], р = 0,018), частота поступления в ОРИТ 14 (26 %) против 29 (66 %), р = 0,001 соответственно. В группе циклоспорина на 7-й день более 75 % поражения легочной ткани, по данным компьютерной томографии, было у 26 % пациентов против 52 % в группе сравнения, р = 0,014, потребность в респираторной поддержке (37 % против 63,6 %, р = 0,011); сатурация 88 (82–93 %) против 80 (70–86 %), р = 0,001 соответственно. Необходимость в респираторной поддержке на 11-й день после применения ИИЛ-6 повышала вероятность летального исхода (ОР 7,12 [2,51–20,10], р = 0,001). Факторы риска летального исхода: возраст старше 57,5 года, индекс массы тела более 30 кг/м2, сатурация ниже 85,5 % в день применения ИИЛ-6. Длительность госпитализации составила 18,5 (14–24) дня против 18 (12–24) дней, р = 0,778. ВЫВОДЫ: Циклоспорин А в дополнение к ГКС и ИИЛ-6 для терапии COVID-19 может способствовать снижению летальности, частоты поступления в ОРИТ и потребности в респираторной поддержке

The next-generation ARC middleware

The Advanced Resource Connector (ARC) is a light-weight, non-intrusive, simple yet powerful Grid middleware capable of connecting highly heterogeneous computing and storage resources. ARC aims at providing general purpose, flexible, collaborative computing environments suitable for a range of uses, both in science and business. The server side offers the fundamental job execution management, information and data capabilities required for a Grid. Users are provided with an easy to install and use client which provides a basic toolbox for job- and data management. The KnowARC project developed the next-generation ARC middleware, implemented as Web Services with the aim of standard-compliant interoperability

Влияние раннего назначения тоцилизумаба на прогрессирование дыхательной недостаточности у пациентов с COVID-19

The optimal interval for initiating tocilizumab therapy in patients with COVID-19 (COronaVIrus Disease 2019) has not been determined. The aim of the study was to evaluate the effectiveness of prescribing tocilizumab depending on the duration of persistent hyperthermia > 38 °С in patients with SARS-CoV-2 (Severe Acute Respiratory Syndrome-related CoronaVirus 2) associated pneumonia who received tocilizumab according to the Interim Guidelines of the Ministry of Health of the Russian Federation (version at the time of inclusion in the study). Methods. A retrospective cohort study was conducted in hospitalized patients (n = 163) with SARS-CoV-2-associated pneumonia from May 2020 to May 2021. Patients were retrospectively divided into 2 groups depending on the time of tocilizumab administration: ≤ 7 days (n = 61) or ≥ 8 days (n = 102) from the disease onset. Results. Patients who received tocilizumab in the first 7 days had the lower need for CPAP (Continuous Positive Airway Pressure) therapy on day 3 after tocilizumab therapy (HR (Hazard Ratio) – 0.129 (0.039 – 0.430); p = 0.001), a higher probability of a decrease in the volume of lung lesions on computed tomography > 25% a week after the use of tocilizumab (HR – 1.065 (1.036 – 1.093); p = 0.001), the lower probability of hemoglobin oxygen saturation below 92% on day 3 (HR – 0.807 (0.750 – 0.869); p = 0.001), and day 7 (HR – 0.825 (0.772 – 0.883); p = 0.001) after tocilizumab therapy. If CPAP therapy was required on day 3 after administration of tocilizumab, each day of delay in prescribing the drug increased the risk of an adverse outcome 18-fold (HR – 18.24 (5.328 – 62.438); p = 0.001). The duration of hospitalization was significantly lower in the early group than in the late group (10 (8.5 – 15) vs 13.5 (10 – 18) days, respectively; p = 0.02). The mortality was similar (5 (8.2%) vs 6 (5.9%) patients, respectively; p = 0.748). Conclusion. The administration of tocilizumab in the first seven days from the onset of the disease in patients with COVID-19 who developed systemic inflammation and lung damage may prevent the need for escalation of respiratory support and accelerate recovery compared with the later tocilizumab administration.Оптимальный интервал для начала терапии тоцилизумабом у пациентов с COVID-19 (COronaVIrus Disease 2019) не определен. Целью исследования явилась оценка эффективности назначения тоцилизумаба в зависимости от продолжительности стойкой гипертермии > 38 °С у пациентов с пневмонией, ассоциированной с SARS-CoV-2 (Severe Acute Respiratory Syndrome-related CoronaVirus 2), получающих терапию тоцилизумабом согласно Временным методическим рекомендациям Министерства здравоохранения Российской Федерации (версия на момент включения в исследование). Материалы и методы. В период с мая 2020 по май 2021 г. проведено ретроспективное когортное исследование с участием госпитализированных пациентов (n = 163) с SARS-CoV-2-ассоциированной пневмонией. Пациенты были ретроспективно распределены на 2 группы в зависимости от времени назначения тоцилизумаба (≤ 7 (n = 61) или ≥ 8 (n = 102) дней от начала заболевания). Результаты. У пациентов, получивших тоцилизумаб в первые 7 дней, ниже необходимость в СРАР-терапии (поддержание постоянного положительного давления в дыхательных путях (Continuous Positive Airway Pressure – СРАР)) (отношение рисков (ОР) – 0,129 (0,039–0,430); р = 0,001) на 3-и сутки после терапии тоцилизумабом; выше вероятность снижения объема поражения легких по данным компьютерной томографии > 25 % через 1 нед. после применения тоцилизумаба (OP – 1,065 (1,036–1,093); р = 0,001); ниже вероятность насыщения гемоглобина кислородом < 92 % на 3-й (OP – 0,807 (0,750–0,869); р = 0,001) и 7-й (OP – 0,825 (0,772–0,883); р = 0,001) дни после терапии тоцилизумабом. При необходимости в СРАР-терапии на 3-й день после введения тоцилизумаба каждый день задержки назначения препарата увеличивал риск неблагоприятного исхода в 18 раз (OP – 18,24 (5,328–62,438); р = 0,001). Продолжительность госпитализации была значимо ниже в группе раннего назначения препарата, чем в группе позднего назначения (10 (8,5–15) дней vs 13,5 (10–18) дня соответственно; р = 0,02). Летальность в группах была одинаковой (5 (8,2 %) vs 6 (5,9 %) пациентов соответственно; р = 0,748). Заключение. У пациентов с COVID-19 при развитии системного воспаления и поражения легких назначение тоцилизумаба в первые 7 дней от начала заболевания по сравнению с более поздним назначением может предотвратить необходимость эскалации респираторной поддержки и ускорить выздоровление

Expression of Gast, Cckbr, Reg1α genes in rat duodenal epithelial cells upon long-term gastric hypoacidity and after a multiprobiotic administration

Aim. Determination of the Cckbr, Gast and Reg1α genes expression in rat duodenal epithelial cells upon long- term hypoacidity and with the administration of the multiprobiotic Symbiter. Methods. The experiments were carried out on white non-strain male rats. The hypoacidic state was induced through intraperitoneal injection of omeprazole for 28 days. The level of genes expression was determined by semi-quantitative analysis with RT-PCR Results. The elevation of mRNA levels of the Cckbr and Gast genes in rat duodenal villus and crypt epitheliocytes, the increased expression of the Reg1A gene in crypt epithelial cells were shown as well as the appearance of the Reg1a gene expression in villus epitheliocytes upon hypoacidic conditions were shown. The content of mRNAs of the above mentioned genes decreased or remained at the control level upon the treatment of hypoacidic rats with the multiprobiotic Symbiter. Conclusions. Long-term gastric hypoacidity is accompanied by the changes in expression of the Cckbr, Gast and Reg1a genes in rat duodenum, whereas upon administration of the multiprobiotic Symbiter the pattern of studied gene expression did not changed in the most cases

Early Cambrian Syenite and Monzonite Magmatism in the Southeast of the East European Platform: Petrogenesis and Tectonic Setting

© 2019, Pleiades Publishing, Ltd. Abstract—The paper reports new geochronological, petrological, and isotope-geochemical data on the syenites and alkali syenites of the Artyushki massif, and the monzonites of the Gusikha massif. These massifs are located along the southwestern and northeastern margins of the Pachelma aulacogen, in the southeastern part of the East European Platform (EEP). They have Early Cambrian ages of 524 ± 3 (Artyushki) and 514 ± 2 Ma (Gusikha) obtained by the U-Pb zircon method and similar ages of amphibole and K-feldspar by the 40Ar/39Ar method. This time period has previously been regarded as amagmatic in the EEP evolution. The Artyushki massif is made up of Amp–Cpx syenite porphyries and Grt–Cpx alkali syenite porphyries and their fenitized varieties. As compared to the Amp–Cpx varieties the Grt–Cpx rocks are more peralkaline (A/NK > 0.9) and have higher LREE and HFSE, and fractionated HREE patterns. The metasomatized (fenitized) varieties are more potassic and bear geochemical evidence of fluid reworking (high Y/Ho ratios, significant Zn variations, and etc.). Bulk samples have weakly radiogenic Sr isotopic compositions: (87Sr/86Sr)520 are within 0.703066–0.703615. The values of εNd(520) vary from –0.69 to +1.64. The Grt–Cpx syenite porphyries have the positive εNd(520), while the Amp–Cpx and fenitized syenite porphyries feature negative εNd. The Gusikha massif consists of biotite–amphibole and biotite monzonites. Similar to the Artyushki syenites in SiO2 contents, the Gusikha monzonites have higher Mg# (0.22–0.54 and 0.34–0.71 for the Artyushki and Gusikha massifs, respectively). They are also characterized by a negative Nb–Ta anomaly (Nb/Nb* = 0.5), high Ва/Sr ratio, and highly radiogenic (87Sr/86Sr)520 = 0.705204 and 0.705320. Their Nd-isotopic compositions correspond to εNd(520) = –6.7 and ‒7.0. Two melts contributed to the formation of the Artyushki massif. One was a strongly contaminated melt (Amp–Cpx syenite porphyries, the other was weakly contaminated (Grt–Cpx syenite porphyries). The main contribution was phonolitic melt derived from the melting of a moderately metasomatized (carbonate- and amphibole-bearing) shallow lithospheric mantle. The earliest and deepest melt portions were carbonate–silicate in composition. The geochemical, as well as the Sr and Nd isotopic compositions of the Gusikha monzonites indicate a predominant crustal contribution and pervasive reworking of the lithospheric mantle beneath southeastern Volgo–Uralia of the EEP in the Mesoproterozoic. Both massifs feature the geochemistry of within-plate and supra-subduction derivatives, which suggests a postorogenic tectonic setting of the magmatism. The presence of the Early Cambrian postorogenic magmatism within the East European Platform/Baltica is direct evidence for the involvement of Baltica in the collisional and/or accretionary events during the terminal Neoproterozoic–the beginning of the Paleozoic. This suggests reworking of the lithospheric mantle of Baltica during its collision with Timanian and East Avalonian/Cadomian terranes, including Scythia

Early Cambrian Syenite and Monzonite Magmatism in the Southeast of the East European Platform: Petrogenesis and Tectonic Setting

© 2019, Pleiades Publishing, Ltd. Abstract—The paper reports new geochronological, petrological, and isotope-geochemical data on the syenites and alkali syenites of the Artyushki massif, and the monzonites of the Gusikha massif. These massifs are located along the southwestern and northeastern margins of the Pachelma aulacogen, in the southeastern part of the East European Platform (EEP). They have Early Cambrian ages of 524 ± 3 (Artyushki) and 514 ± 2 Ma (Gusikha) obtained by the U-Pb zircon method and similar ages of amphibole and K-feldspar by the 40Ar/39Ar method. This time period has previously been regarded as amagmatic in the EEP evolution. The Artyushki massif is made up of Amp–Cpx syenite porphyries and Grt–Cpx alkali syenite porphyries and their fenitized varieties. As compared to the Amp–Cpx varieties the Grt–Cpx rocks are more peralkaline (A/NK > 0.9) and have higher LREE and HFSE, and fractionated HREE patterns. The metasomatized (fenitized) varieties are more potassic and bear geochemical evidence of fluid reworking (high Y/Ho ratios, significant Zn variations, and etc.). Bulk samples have weakly radiogenic Sr isotopic compositions: (87Sr/86Sr)520 are within 0.703066–0.703615. The values of εNd(520) vary from –0.69 to +1.64. The Grt–Cpx syenite porphyries have the positive εNd(520), while the Amp–Cpx and fenitized syenite porphyries feature negative εNd. The Gusikha massif consists of biotite–amphibole and biotite monzonites. Similar to the Artyushki syenites in SiO2 contents, the Gusikha monzonites have higher Mg# (0.22–0.54 and 0.34–0.71 for the Artyushki and Gusikha massifs, respectively). They are also characterized by a negative Nb–Ta anomaly (Nb/Nb* = 0.5), high Ва/Sr ratio, and highly radiogenic (87Sr/86Sr)520 = 0.705204 and 0.705320. Their Nd-isotopic compositions correspond to εNd(520) = –6.7 and ‒7.0. Two melts contributed to the formation of the Artyushki massif. One was a strongly contaminated melt (Amp–Cpx syenite porphyries, the other was weakly contaminated (Grt–Cpx syenite porphyries). The main contribution was phonolitic melt derived from the melting of a moderately metasomatized (carbonate- and amphibole-bearing) shallow lithospheric mantle. The earliest and deepest melt portions were carbonate–silicate in composition. The geochemical, as well as the Sr and Nd isotopic compositions of the Gusikha monzonites indicate a predominant crustal contribution and pervasive reworking of the lithospheric mantle beneath southeastern Volgo–Uralia of the EEP in the Mesoproterozoic. Both massifs feature the geochemistry of within-plate and supra-subduction derivatives, which suggests a postorogenic tectonic setting of the magmatism. The presence of the Early Cambrian postorogenic magmatism within the East European Platform/Baltica is direct evidence for the involvement of Baltica in the collisional and/or accretionary events during the terminal Neoproterozoic–the beginning of the Paleozoic. This suggests reworking of the lithospheric mantle of Baltica during its collision with Timanian and East Avalonian/Cadomian terranes, including Scythia