Ruxolitinib versus dexamethasone in hospitalized adults with COVID-19: multicenter matched cohort study.

BACKGROUND: Several anti-cytokine therapies were tested in the randomized trials in hospitalized patients with severe acute respiratory syndrome coronavirus 2 infection (COVID-19). Previously, dexamethasone demonstrated a reduction of case-fatality rate in hospitalized patients with respiratory failure. In this matched control study we compared dexamethasone to a Janus kinase inhibitor, ruxolitinib. METHODS: The matched cohort study included 146 hospitalized patients with COVID-19 and oxygen support requirement. The control group was selected 1:1 from 1355 dexamethasone-treated patients and was matched by main clinical and laboratory parameters predicting survival. Recruitment period was April 7, 2020 through September 9, 2020. RESULTS: Ruxolitinib treatment in the general cohort of patients was associated with case-fatality rate similar to dexamethasone treatment: 9.6% (95% CI [4.6-14.6%]) vs 13.0% (95% CI [7.5-18.5%]) respectively (p = 0.35, OR = 0.71, 95% CI [0.31-1.57]). Median time to discharge without oxygen support requirement was also not different between these groups: 13 vs. 11 days (p = 0.13). Subgroup analysis without adjustment for multiple comparisons demonstrated a reduced case-fatality rate in ruxolitnib-treated patients with a high fever (≥ 38.5 °C) (OR 0.33, 95% CI [0.11-1.00]). Except higher incidence of grade 1 thrombocytopenia (37% vs 23%, p = 0.042), ruxolitinib therapy was associated with a better safety profile due to a reduced rate of severe cardiovascular adverse events (6.8% vs 15%, p = 0.025). For 32 patients from ruxolitinib group (21.9%) with ongoing progression of respiratory failure after 72 h of treatment, additional anti-cytokine therapy was prescribed (8-16 mg dexamethasone). CONCLUSIONS: Ruxolitinib may be an alternative initial anti-cytokine therapy with comparable effectiveness in patients with potential risks of steroid administration. Patients with a high fever (≥ 38.5 °C) at admission may potentially benefit from ruxolitinib administration. Trial registration The Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very Severe COVID-19 Illness NCT04337359, CINC424A2001M, registered April, 7, 2020. First participant was recruited after registration date.

[Monoclonal gammopathy of renal significance: consensus of hematologists and nephrologists of Russia on the establishment of nosology, diagnostic approach and rationale for clone specific treatment].

Monoclonal gammopathy of renal significance (MGRS) is a new nosology in modern nephrology and oncohematology. MGRS is defined as kidney injury due to nephrotoxic monoclonal immunoglobulin produced by the B-cell line clone which does not reach the hematological criteria for specific treatment initiation. Monoclonal proteins pathological effects on kidney parenchyma result in irreversible decline of kidney function till the end stage renal disease that in line with the position of International Consensus of hematologists and nephrologists determinates critical necessity for clone specific treatment in patients with MGRS despite the absence of hematological indications for treatment initiation. Main challenge of MGRS in Russian Federation is an inaccessibility of an in-time diagnostic and appropriate treatment for the great majority of patients due to the following reasons: 1) limited knowledge about the MGRS among hematologists and nephrologists; 2) lack of necessary diagnostic resources in most health-care facilities; 3) lack of approved clinical recommendations and medical economic standards for treatment of this pathological entity. Consensus document comprises the opinion of experts leading nephrologists and hematologists of Russian Federation on the problem of MGRS including the incoherence in nosology classification, diagnostics approach and rationale for clone specific treatment. Consensus document is based on conclusions and agreements reached during the conference of leading nephrologists and hematologists of Russia which was held in the framework of symposia Plasma cell dyscrasias and lymphoproliferative diseases: modern approaches to therapy, 1516 of March 2019, Pavlov First Saint Petersburg State Medical University. The present Consensus is intended to define the principal practical steps to resolve the problem of MGRS in Russian Federation that are summarized as final clauses.

[Fecal microbiota transplantation for graft-versus-host disease in children and adults: methods, clinical effects, safety].

AIM: Was to evaluate clinical efficacy, adverse events and changes in the gut microbiome after fecal microbiota transplantation (FMT) in patients with gastrointestinal (GI) form of graft-versus-host disease (GVHD). MATERIALS AND METHODS: The prospective single-center study in R.M. Gorbacheva institute included 27 patients with GI GVHD after allogeneic stem cell transplantation. 19 patients received FMT, 8 patients received placebo. Clinical scales for GI autoimmune diseases were used to evaluate response. Microbiome alterations were assessed with multiplex PCR. RESULTS: After FMT higher overall bacterial mass (р=0.00088), higher bacterial numbers ofBifidobacteriumspp. (р=0.021),Escherichia coli(р=0.049) andBacteroides fragilisgr. (р=0.000043) compared to placebo group. Also higher bacterial mass was observed in patients with clinical response (р=0.0057). The bacterial mass after procedure in non-responders was compared to the placebo group (р=0.31). Partial response of GVHD was achieved faster in the FMT group compared to placebo (median 4 days vs 48 days,p=0.014). Complete response was observed in 8 (42%), 14 (74%) and 16 (84%) at 30, 60 and 90 days respectively, while in the placebo group only 0%, 1 (13%) and 4 (50%) achieved complete response at the same time points. The incidence and severity of adverse events was comparable between FMT and the placebo group. CONCLUSION: FMT in patients with refractory GI GVHD was associated with favorable clinical outcomes and recovery in certain marker bacterial populations. Multiplex PCR can be used to assess an engraftment of a donor microbiota. FMT in GI GVHD was not associated with life-threatening adverse events, but further studies are required to validate clinical efficacy.

[Rhinosinusitis in Hurler syndrome patients requiring hematopoietic stem cells transplantation]. / Problema rinosinusita u patsientov s sindromom Gurler pri transplantatsii gemopoéticheskikh stvolovykh kletok.

INTRODUCTION: Allogenic transplantation of hemopoetic stem cells (allo-THSC) is one of the most effective treatment methods for Hurler syndrome, aimed at maximal correction of complications related to the genetic disorder. Presence of infection in the recipient is an adverse risk factor, affecting the possibility of starting the conditioning regimen and THSC peforming in general. AIM: To assess the condition of the nasal cavity and paranasal sinuses in Hurler syndrome patients before the allo-THSC, dynamics of these changes after the transplantation taking into account the correction of alpha-L-iduronidase enzyme level with donor blood cells. MATERIAL AND METHODS: From February 2012 to December 2017, In the Raisa Gorbacheva Research Institute of Child Oncology, Hematology and Transplantology of the Pavlov First Saint Petersburg State Medical University, eighteen Hurler syndrome patients (10 girls and 8 boys) received an allo-THSC. Median age at the time of the procedure was 23,5 months (min - 3,4; max - 24,8). Each patient with the shadowing of paranasal sinuses, rhinitis or nasal breathing difficulty received a standard rhinosinusitis treatment before the transplantation, effect of which was insignificant. Symptoms of rhinitis, condition of pharyngeal tonsil and paranasal sinuses were assessed before and auto the allo-THSC. RESULTS: In the post-allo-THSC, with the correction of alpha-L-iduronidase level each evaluated parameter has improved reliably (p-value < 0,05). Comparative analysis of the condition of the nasal cavity and pharyngeal tonsil before and after THSC was conducted on 14 patients out of 18. Rhinitis symptoms decreased in 9 (64,2%) patients; in 11 patients (78,5%) adenoids size reduced. Comparative analysis of the condition of paranasal sinuses was possible in 12 patients out of 18. Sinuses aeration improved in eight (66,6%) if patients. CONCLUSION: Nasal cavity and paranasal sinuses changes in Hurler syndrome patients before and after allo-THSC is poorly studied. Our experience demonstrates the normalization of nasal cavity, pharyngeal tonsila and paranasal sinuses symptoms in the majority of the patients receiving allo-THSC. These symptoms are, it seems a consequence of the underlying disease.

Profiles of pro-inflammatory cytokines in allogenic stem cell transplantation with post-transplant cyclophosphamide.

Large number of studies was published about predictive value of cytokines for graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Recently, there has been a growing interest in GVHD prophylaxis with post-transplant cyclophosphamide (PTCy). Clinical data on the dynamics of proinflammatory cytokines with this prophylaxis is lacking. In this study, we have measured the levels of IL-17, IL-6, IL-8, IFN-γ and TNF-α in plasma on days -7, 0, +7, +14 and after engraftment in 20 patients with acute GVHD and 40 matched control patients with PTCy-based prophylaxis. Low levels of IL-8 (p=0.04) on day +7 and IFN-γ (p=0.03) after engraftment were associated with grade II-IV acute GVHD. The same pattern was observed for severe acute GVHD. Low IFN-γ after engraftment was also associated with increased non-relapse mortality (p=0.014). No impact of cytokine levels on overall survival and relapse incidence was observed (p>0.05). In conclusion, the dynamics of IL-8 and IFN-γ in GVHD patients after PTCy was different from previously reported after conventional prophylaxis.

Artificial intelligence methods to estimate overall mortality and non-relapse mortality following allogeneic HCT in the modern era: an EBMT-TCWP study.

Allogeneic haematopoietic cell transplantation (alloHCT) has curative potential counterbalanced by its toxicity. Prognostic scores fail to include current era patients and alternative donors. We examined adult patients from the EBMT registry who underwent alloHCT between 2010 and 2019 for oncohaematological disease. Our primary objective was to develop a new prognostic score for overall mortality (OM), with a secondary objective of predicting non-relapse mortality (NRM) using the OM score. AI techniques were employed. The model for OM was trained, optimized, and validated using 70%, 15%, and 15% of the data set, respectively. The top models, "gradient boosting" for OM (AUC = 0.64) and "elasticnet" for NRM (AUC = 0.62), were selected. The analysis included 33,927 patients. In the final prognostic model, patients with the lowest score had a 2-year OM and NRM of 18 and 13%, respectively, while those with the highest score had a 2-year OM and NRM of 82 and 93%, respectively. The results were consistent in the subset of the haploidentical cohort (n = 4386). Our score effectively stratifies the risk of OM and NRM in the current era but do not significantly improve mortality prediction. Future prognostic scores can benefit from identifying biological or dynamic markers post alloHCT.

Long-term outcomes of ruxolitinib therapy in steroid-refractory graft-versus-host disease in children and adults.

Acute and chronic steroid-refractory graft-versus-host disease (srGVHD) is a life-threatening complication of allogeneic stem cell transplantation. There are a number of reports on case series describing efficacy of ruxolitinib in both acute and chronic srGVHD. We conducted a prospective study (NCT02997280) in 75 patients with srGVHD (32 acute, 43 chronic, 41 adults, and 34 children). Patients with chronic GVHD had severe disease in 83% of cases, and acute GVHD patients had grade III-IV disease in 66% of cases. The overall response rate (ORR) was 75% (95% CI 57-89%) in acute GVHD and 81% (95% CI 67-92%) in chronic. Overall survival was 59% (95% CI 49-74%) in acute group and 85% (95% CI 70-93%). The major risk factors for lower survival were grade III-IV gastrointestinal involvement (29% vs 93%, p = 0.0001) in acute form and high disease risk score in chronic (65% vs 90%, p = 0.038). Toxicity was predominantly hematologic with 79% and 44% of grade III-IV neutropenia in acute and chronic groups, respectively. There was no difference between adults and children in terms of ORR (p = 0.31, p = 0.35), survival (p = 0.44, p = 0.12) and toxicity (p > 0.93). The study demonstrated that ruxolitinib is an effective option in acute and chronic srGVHD and can be used both in adults and children.

Sodium hydroxide and sodium tripolyphosphate effects on bind strength and sensory characteristics of restructured beef rolls.

Restructured beef rolls formulated with 1% NaCl (controls) or with 1% NaCl plus 0.07% NaOH or 0.375% sodium tripolyphosphate (STPP) had different (p < 0.05) relative bind strength and cooked yield, as follows: STPP > NaOH > controls. Percent cooked yield was inversely affected (p < 0.05) by added water level (5 > 10 > 20%). Bind values were lower (p < 0.05) in rolls with 20% added water. NaOH and STPP rolls had higher pH (p < 0.05) than controls (6.28, 6.22, and 6.07, respectively). Panel cohesiveness, juiciness, and acceptability scores were also generally higher (p < 0.05) for NaOH and STPP rolls, compared to controls. There was a high correlation (0.93) between panel cohesiveness scores and instrumental bind values. At 20% added water, STPP rolls were preferred, but at 10% added water, STPP and NaOH rolls were similar in overall acceptability. Thus, if added water level is not too high, NaOH alone or perhaps with other binding agents may be an alternative to phosphates in cooked beef rolls.

Minimum sodium nitrite levels for pinking of various cooked meats as related to use of direct or indirect-dried soy isolates in poultry rolls.

The relationship between sodium nitrite level and pinking was investigated in cooked meats, as measured by panel color score, acetone extraction of NO-hemochrome, and instrumental redness values. Beef was less susceptible than poultry breast meat to nitrite-induced pinking. Minimum sodium nitrite level for pinking was 14, 4, 2, and 1 ppm for beef round, pork shoulder, turkey breast, and chicken breast, respectively. By regression analysis, minimum ppm nitrite for pinking=0.092 (ppm total pigment)+0.53 (R(2)=0.99). High levels of nitrate (>250 ppm as sodium nitrate) and nitrite (>45 ppm as sodium nitrite) were found in direct-dried (DD) soy isolates. Chicken breast rolls formulated with >2% DD soy were pink, but control rolls with 156 ppm sodium nitrate were not pink. Thus, it was concluded that nitrite was the primary pinking agent in DD soy. Indirect-dried (ID) soy isolates contained <11 ppm sodium nitrite, which was insufficient for pinking in poultry rolls.

[3-substituted analogs of remantadine: synthesis and antiherpetic activity in Vero cells]. / 3-zameshchennye analogi remantadina: sintez i protivogerpeticheskaia aktivnost' v kul'ture kletok Vero.

Chemical synthesis of 3-substituted analogues of remantadine is described. Derivatives IIIb and IIIc when compared with remantadine had not only potent activity against ethalon herpes simplex type 1 virus strain but also were active against herpes virus resistant to aciclovir. Compound IIIc demonstrated virulecidal effect. Combination of IIIc + aciclovir had additive effect against ethalon herpes simplex type 1 virus strain. Investigated 3-substituted analogues demonstrated low activity in the model system of influenzae virus. No antiviral activity was demonstrated in the model system of Syndbys virus (though compounds were evaluated in subtoxic concentrations).

[The histomorphological changes in the mucosa of the edges of the cleft palate and their effect on surgical wound healing]. / Gistomorfologicheskie izmeneniia slizistoi obolochki kraev nesrashcheniia neba i ikh vliianie na zazhivlenie operatsionnoi rany.

The study has involved 30 children aged 4 to 6 with cleft lip and palate. Histomorphologic changes of soft tissues on cleft palate edges were detected; these inflammatory dystrophic changes are associated with reduction of the body nonspecific reactivity.

[Nicotinamide correction of the oxidative metabolism of cerebral cortex cells in the kindling phenomenon]. / Korrektsiia nikotinamidom okislitel'nogo obmena kletok kory golovnogo mozga pri fenomene "raskachki".

A corrective effect of Nicotinamide on oxidation processes in ganglion and neuroglial cells of cerebral cortex sensorimotor zone in "kindling" phenomenon was studied in the experiments on mice of C57BL line. The kindling was caused by daily injection of Corazol in a dose of 30 micrograms/kg intraperitoneally during one month. The experimental mice were introduced Corazol by the same scheme but beginning from the 4th week Nicotinamide was injected daily/5, 50, 200 mg/kg intraperitoneally/30 min before Corazol introduction. Cytophotometric investigations of enzyme activity/glytamate-, succinate-, -glycerophosphate, glucose-6-phosphate-dehydrogenase and NADH-tetrazol reductase/showed that the most optimum dose of nicotinamide stimulating the tissue oxidation in the dose of 50 mg/kg. It was also established that nicotinamide in the dose of 50 mg/kg has a definite antispasmodic effect and increases ganglion cells stability to destructive effect of epiphogenic factors.

[Cytophotometric study of changes in glutamate dehydrogenase and GABA transaminase in the cerebral cortex during corazole kindling]. / Tsitofotometricheskoe izuchenie izmenenii glutamatdegidrogenazy i transaminazy GAMK v kore golovnogo mozga pri korazolovom kindlinge.

It has been demonstrated in (CBA X C57BL/6) F1 mice that daily corazole injections (30 mg/kg) lead to the development of pharmacological kindling that manifests in a progressive increase of seizure susceptibility, seizure occurrence in response to the subthreshold convulsant dose and in demonstrable seizures. Cytophotometric study of the histological specimens of the sensorimotor cortex discovered the reduced enzymatic activity of glutamate dehydrogenase and GABA transaminase in the neurons. In the neuroglial cells, the activity of glutamate dehydrogenase also declined, whereas that of GABA transaminase tended on the contrary, towards increase.

Fundamental principles of the behavior of 137Cs in the soil and its migration into agricultural crops.

In this article, we present the results of long-term laboratory and field investigations designed to characterize the dynamics of the various forms of compounds of the radionuclide in the soil in relation to its biological accessibility to plants. The variations in the extent of migration of 137Cs from the soil into the harvested parts of agricultural crops on the most typical soils, the contribution of the processes of fixation of the radionuclide to these variations, and the role of various properties of the soil in the migration of 137Cs into plants and the possible fluctuations in the migration of the radionuclide into plants caused by the interspecific and varietal characteristics of the plants are also discussed. The quantitative characteristics of the migration of 137Cs into the crops determined in vegetation, microfield experiments, and field experiments are compared and the possibilities of extrapolating the results of the experiments of the first two types to natural conditions are demonstrated.

[Various neurochemical aspects of the action of the tetrapeptide tuftsin on limbic system structures (histochemical and biochemical study)]. / Nekotorye neirokhimicheskie aspekty deistviia tetrapeptida taftsina na struktury limbicheskoi sistemy (gistokhimicheskoe i biokhimicheskoe issledovanie).

Tetrapeptide tuftsin action on the activity of succinate dehydrogenase (SDG), malate dehydrogenase (MDG) and monoamine-oxidase (MAO) in microstructures of the neocortex, hippocampus and hypothalamus (supraoptic and paraventricular nuclei, retrochiasmic zone) has been investigated by means of histochemical methods. Simultaneously, pyruvate-, malate-, glutamate-, alfaketoglutamate-, succinate- and lactate-dehydrogenase activity in the neocortex and in the structures of the limbic system has been studied biochemically. SDG and MDG activity increases in neurons and glycocytes of all the hypothalamic formations mentioned. Changes in the activity of dehydrogenases in the hippocampus and neocortex under the same stimulation are less pronounced. MAO activity also increases in the nerve terminals converging on the bodies and dendrites of hypothalamic neurons and in the preterminal fibers of the neocortex, Tuftsin increases oxidative-reducing processes in various structures of the brain, but at the same time it possesses a predominant influence on the limbic system structures.

[Changes in the spectrum of LDH isoenzymes in foci of epileptic activity induced by penicillin in the cerebral cortex of rats]. / Izmeneiia spektra izofermentov LDG v ochagakh épilepticheskoi aktivnosti, vyzvannykh penitsillinom v kore golovnogo mozga krys.

The correlation between electrophysiological changes and isozymes of LDH of the rat brain cortex was studied in seizure foci induced by application of sodium penicillin. It was discovered that activity of LDH1 was suppressed, and that of LDH5 fraction was elevated in the determinant focus, which indicates the enhanced glucose anaerobic transformation. The spectrum of LDH isozymes did not practically differ from the indicators in control animals in a homotopic region of the contralateral hemisphere prior to creation of the mirror focus. The anaerobic processes were found to be increased in the mirror focus and in the determinant one as well. Similar pattern of changes in electrophysiological and neurochemical characteristics in the determinant and dependent mirror foci attests to the formation of a pathological system out of the two epileptic foci.

[Changes in the dehydrogenase and GABA transaminase activity in the cerebral cortex during corazol kindling]. / Dinamika aktivnosti nekotorykh degidrogenaz i transaminazy GAMK v kore bol'shogo mozga pri korazolovom kindlinge.

The experiments on (CBA X C57BL/6)F1 mice have shown that regular corazol injections in subliminal doses stimulated seizure susceptibility (pharmacological kindling). Cytophotometric assay of the activity of oxidative metabolism enzymes (glutamate dehydrogenase, malate dehydrogenase, succinate dehydrogenase, alpha-oxoglutarate dehydrogenase, lactate dehydrogenase) and GABA-transaminase in the sensorimotor cortex of kindled mice in post-convulsive period, and 24 hours or 30 days after corazol injections were discontinued, has revealed some specific alterations of the enzymes under study, that suggest the existence of two phases of energy metabolism disturbances. The first phase (24 hours after corazol injections were discontinued) is characterized by intensified succinic acid oxidation, while the second phase (30 days after the last injection) is characterized by anaerobic glycolysis in neuronal and glial cells. Inhibition of GABA-transaminase activity was particularly marked in postconvulsive period. From a molecular point of view these data may be considered as enzyme disturbances during stimulation of seizure susceptability or seizure activity and as a compensation component ensuring anticonvulsive mechanisms and reparative processes (antagonistic principle of molecular mechanism regulation) during activation of antiepileptic system.

[Changes of the dehydrogenase activity in the hippocampus in the korazol-induced kindling phenomenon]. / Izmeneniia aktivnosti degidrogenaz v gippokampe pri indutsirovannom korazolom fenomene raskachki.

The activity of glutamate, succinate, malate and lactate dehydrogenases in neuronal and glial hippocampal cells during corazol kindling has been cytophotometrically assessed in the experiments on (CBA X C57BL/6)F1 mice. The kindling was induced by regular intraperitoneal corazol injections in subliminal dose of 30 mg/kg. Histochemical investigations were performed 30 min, 24 hours and 30 days after the corazol injections were discontinued. The changes in the enzymatic activity revealed suggest the biphasic nature of the disturbances in energy metabolism. During the first phase (24 hours after the last injection) the enzymatic changes do not have a noticeable influence on the predominant aerobic type of oxidation. In the second phase (30 days after the last injection) lactate dehydrogenase activity significantly increases, while the activity of other enzymes under study reduces.

[Effect of destruction of the hippocampus and caudate nucleus on the development of epileptic activity during corazole kindling]. / Vliianie razrusheniia gippokampa i khvostatogo iadra na razvitie épilepticheskoi aktivnosti pri korazolovom kindlinge.

Experiments were carried out on random-bred white rats (250-350 g). Kindling was induced by daily intraperitoneal corazol injections in subthreshold (subconvulsive) doses (30 mg/kg). It has been demonstrated that bilateral hippocampal destruction did not change the seizure threshold, while bilateral caudate nucleus destruction lowered it. Hippocampal destruction delayed corazol kindling development and also accelerated the lowering of seizure susceptibility after corazol injections were discontinued, as compared to control animals. Caudate nucleus destruction induced more marked seizure reactions in the first 14 days after corazol injections were started. There were no significant differences in seizure manifestation severity in kindled and control groups. These data point to an essential role of caudate nucleus as an element of antiepileptic system and support the concept that hippocampus plays a role of pathologic determinant which is associated with the formation of an epileptic system underlying corazol kindling.